Microwave-assisted synthesis and anti-HIV activity of new acyclic C-nucleosides of 3-(D-ribo-tetritol-1-yl)-5-mercapto-1,2,4-triazoles. Part 1

Article abstract of DOI:10.1080/15257770802088829

Microwave-assisted synthesis of novel acyclic C-nucleosides of 6-alkyl/aryl-3-(1,2-O-isopropylidene-D-ribo-tetritol-1-yl)[1,2,4]triazolo[3,4-b] [1,3,4]thiadiazoles (5-12) and the 6-aryl-thiomethyl analogues 25-27 has been described. Deblocking of 5-12 and 25-27 afforded the free acyclic C-nucleosides 13-20, and 28-30, respectively. All of the synthesized compounds showed no inhibition against HIV-1 and HIV-2 replication in MT-4 cells. However, 6-(3,4-dichlorophenyl)-3-(1,2-O-isopropylidene-D-ribo-tetritol-1-yl)-7H-1,2, 4-triazolo[3,4-b][1,3,4]thiadiazole (6) is a potent inhibitor, in vitro, of the replication of HIV-2. These results suggest that compound 6 should be considered as a new lead in the development of antiviral agent. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/15257770802088829

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Microwave-Assisted Synthesis and
Anti-HIV Activity of New Acyclic C-
Nucleosides of 3-(D-Ribo-Tetritol-1-yl)-5-
Mercapto-1,2,4-Triazoles. Part 1
Yaseen A. Al-Soud a , Najim A. Al-Masoudi b , Thilo Schuppler b , Erik
De Clercq c & Christophe Pannecouque c
a Department of Chemistry, College of Science, University of Al al-
Bayt, Al-Mafraq, Jordan
b Fachbereich Chemie, Universität Konstanz, Postfach Konstanz,
Germany (formerly)
c Rega Institute for Medical Research, Katholieke Universiteit
Leuven, B-3000, Leuven, Belgium
Version of record first published: 19 Jun 2008.
To cite this article: Yaseen A. Al-Soud , Najim A. Al-Masoudi , Thilo Schuppler , Erik De Clercq &
Christophe Pannecouque (2008): Microwave-Assisted Synthesis and Anti-HIV Activity of New Acyclic C-
Nucleosides of 3-(D-Ribo-Tetritol-1-yl)-5-Mercapto-1,2,4-Triazoles. Part 1, Nucleosides, Nucleotides
and Nucleic Acids, 27:5, 469-483
To link to this article: http://dx.doi.org/10.1080/15257770802088829
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Nucleosides, Nucleotides and Nucleic Acids, 27:469–483, 2008
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770802088829
MICROWAVE-ASSISTED SYNTHESIS AND ANTI-HIV ACTIVITY OF
NEW ACYCLIC C-NUCLEOSIDES OF 3-(D-RIBO-TETRITOL-1-YL)-
5-MERCAPTO-1,2,4-TRIAZOLES. PART 1
Yaseen A. Al-Soud,1 Najim A. Al-Masoudi,2 Thilo Schuppler,2
Erik De Clercq,3 and Christophe Pannecouque3
1Department of Chemistry, College of Science, University of Al al-Bayt, Al-Mafraq, Jordan
2Fachbereich Chemie, Universita¨t Konstanz, Postfach Konstanz, Germany (formerly)
3Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven,
Belgium
Microwave-assisted synthesis of novel acyclic C-nucleosides of 6-alkyl/aryl-3-(1,2-O-
2
isopropylidene-D-ribo-tetritol-1-yl)[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles (5–12) and the 6-aryl-
thiomethyl analogues 25–27 has been described. Deblocking of 5–12 and 25–27 afforded the free
acyclic C-nucleosides 13–20, and 28–30, respectively. All of the synthesized compounds showed no
inhibition against HIV-1 and HIV-2 replication in MT-4 cells. However, 6-(3,4-dichlorophenyl)-3-
(1,2-O-isopropylidene-D-ribo-tetritol-1-yl)-7H-1,2,4-triazolo[3,4-b][1,3,4]thiadiazole (6) is a potent
inhibitor, in vitro, of the replication of HIV-2. These results suggest that compound 6 should be
considered as a new lead in the development of antiviral agent.
Keywords Anti-HIV activity; acyclic C-nucleosides; microwave-assisted synthesis;
6-substituted-3-(D-ribo-tetritol-1-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles
INTRODUCTION
Recent work has demonstrated the feasibility of using acyclic nucleo-
side analogues as antiviral chemotherapeutic agents. The acyclic purine
derivatives have been the most widely studied.[1–4] For instance, (S)-9-
(2,3-dihydroxypropyl)adenine ((S)-DHPA) 1,[5] the potent antiherpetic
drug[6a,7] acyclovir (ACV, Zovirax),[8,9] 9-(2-phosphonylmethoxyethyl)
adenine (PMEA), (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl) adenine
(HPMPA),[10] (RS)-9-[4-hydroxy-2-(hydroxymethyl)butyl] guanine (HBG)
Received 16 October 2007; accepted 3 March 2008.
This article is dedicated for Professor W. Pfleiderer on the occasion of his 80th birthday.
Address correspondence to Najim A. Al-Masoudi, P.O. Box 100552, 78405 Konstanz, Germany.
E-mail: Najim.Al-Masoudi@gmx.de
469

470
Y. A. Al-Soud et al.
and 9-[(1,3-dihydroxy-2-propoxy)methyl] guanine (DHPG),[11,12] are ex-
amples of such potent antiviral agents against a number of DNA and
RNA viruses. Structure-activity relationship studies have shown that the side
chains of acyclonucleosides play a crucial role in the interaction of the
acyclonucleosides with their antiviral target enzymes.[13,14]
In addition, compounds containing five-membered heterocyclic bases
are important targets in chemical synthesis because of their pronounced bi-
ological activities. Various substituted 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines
and their schiff bases are associated with diverse pharmacological activities
such as analgesic, antihelmintic, antitubercular, plant growth regulating, an-
tiviral, antifungal, antibacterial, and anticancer properties.[15–19] Recently,
Al-Masoudi et al.[20] have reviewed the synthetic approaches of 1,2,4-
triazoles and their pharmacological importance.
Prompted by the varied biological activities of the acyclic nucle-
osides with 1,2,4-triazole and 1,3,4-thiadiazole rings, and as a contin-
uation of our recent work on the synthesis of acyclic N - and C-
nucleosides,[25–30] we herein report on the synthesis of novel acyclic 6-
alkyl/aryl-and 6-thioarylthiomethyl-3-(1,2-O-isopropylidene-D-ribo-tetritol-1-
yl)[1,2,4]triazolo[3,4-b][1,3,4] thiadiazoles, and their free nucleosides with
evaluation of their anti-HIV activity.
RESULTS AND DISCUSSION
The required N 4-amino-3-(1,2-O-isopropylidene-D-ribo-tetritol-1-yl)-
5-mercapto-1,2,4-triazole (3) (87%) was prepared by treatment of
the γ -lactone 2 with thiocarbohydrazide in pyridine under microwave
irradiation (MWI) for 15 minutes (Scheme 1). Then, 3 was cyclized with the
appropriate substituted benzoic acids, 2-chloro-, 3,4-dichloro-, 3-amino- and
4-aminobenzoic acids, thiophene-2-carboxylic acid, adamantan-1-carboxylic
acid, coumarin-3-carboxylic acid, and 3-(dimethylamino)benzoic
acid, respectively, in DMF at 120◦C for 45 minutes furnishing the
6-alkyl/aryl-3-(1,2-O-isopropylidene-D-ribo-tetritol-1-yl)[1,2,4]triazolo[3,4-b]

Microwave-Assisted Synthesis of Novel Acyclic C-Nucleosides
471
SCHEME 1 Reagents and conditions (i) (NH2NH)2C S, pyridine, MWI, 15 min; (ii) RCO2H, DMF, MWI,
45 min, 120◦C; (iii) 80% HOAc, 80◦C, 12 h
[1,3,4]thiadiazoles (5–12) in 56–94% yield. Acid hydrolysis of 3, and 5–12
with 80% HOAc at 80◦C for 12 hours afforded the free nucleosides 4 and
13–20 (73% and 66–83% yield, respectively). Acetylation of 14 with acetic
anhydride in pyridine at 23◦C gave the crystalline tertaacetate derivative 21
(83%).
The structures of the newly synthesized compounds 3–20 were assigned
1
by the 1H, 13C NMR and mass spectra. The H NMR spectra of 3 and 5–12
showed rather similar pattern for the 1,2-O-isopropylidene-D-ribose protons
ꢁ
ꢁ
at ∼δ 1.45 and 1.35. Thus, the doublets at δ 4.78–4.84 with J 1 ,2 ∼ 5.5 Hz
were assigned to H-1ꢁ, while the doublets of doublets oriented at the region

472
Y. A. Al-Soud et al.
δ 4.71–4.78 were assigned to H-2ꢁ (J 2 ,3 ∼ 2.3 Hz). The triplets at δ 4.56–4.63
ꢁ
ꢁ
were assigned to H-3ꢁ (J 3 ,4 a ∼ 2.3 Hz), while the doublets of doublets at δ
ꢁ
ꢁ
3.92–3.99 and δ 3.74–3.94 arose due to the geminal H-4ꢁa and H-4ꢁb protons,
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
respectively, (J 3 ,4 a ∼ 2.5 Hz, J 3 ,4 b ∼ 4.5 Hz, J 4 a,4 b ∼ 12.0 Hz). In the
13C NMR spectra of 3, the signals at δ 182.0 and 174.2 were assigned to
C S and C N, while C-6, and C-3 and C-8 of compounds 5–12 appear at δ
174.1–174.9, δ 160.0–171.8 and, δ 141.4–154.1, respectively (except 9, C-6
and C-3 appeared at δ 183.4 and δ 174.9, respectively). The sugar carbons
were fully analysed, where C-1ꢁ appeared at the region δ 78.1–78.3 and
C-2ꢁ at the region δ 82.1–82.8. C-3ꢁ and C-4ꢁ resonate at δ 74.9–75.7, and
δ 60.0–62.1, respectively. The phenyl, adamantan, coumarin, thiophene,
and the isopropylidene carbon atoms were fully assigned (see Experimental
1
section). Similarly, the H-, and 13C NMR spectra of the free nucleosides 4
and 13–20 were well established. The tetraacetate 21 was selected for further
spectroscopic analysis. From the gradient selected HMBC spectrum[27] of
2
21, C-3 at δC 169.8 shows a heteronuclear J C,H correlation to H-1ꢁ at δH
5.73, while C-6 at δC 170.2 shows 3J C,H correlation with the aromatic protons
Hb at δH 8.10 and Hf at δH 7.85, respectively.
Next, our efforts have been focused on the synthesis of 1,2,4-triazolo[3,4-
b][1,3,4]thiadiazin-6-one derivatives as potential pharmacological com-
pounds. Thus, treatment of 3 with 2-bromoacetic acid in DMF under MWI
for 45 minutes afforded a compound tentatively identified as a thiadiazin-6-
one derivative 23 (57%) and not 6-(bromomethyl)-3-(1,2-O-isopropylidene-
D-ribo-tetritol-1-yl)[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole (22) (Scheme 2).
2
The HMBC spectrum of 23 revealed two J C,H correlations between CH2S
at δH 2.81 and C O at δC 175.1, and C-9 at δC 149.9, confirming the
existence of the thiadiazin-6-one ring. These data are in accordance with
the observations of Holla et al.[28] The mass fragmentation pattern was
consistent with the suggested structure, however, the FABMAS spectrum
showed a protonated molecular ion at m/z 317 (M+H)+.
Heating of 23 with aryl mercaptans for 5 h afforded, after pu-
rification, products tentatively identified as 6-arylthio-1,2,4-triazolo[3,4-
b][1,3,4]thiadiazole derivatives 25–27 in 72%, 86%, and 90% yield, respec-
1
tively. The structures of 25–27 were identified from the H-, 13C-NMR and
mass spectra. The sugar protons and carbons showed rather similar pattern
for those of compounds 5–12. CH2S protons resonated as singlets at δH
4.27, 3.09 and 4.11, respectively, while the carbons appeared at δC 40.6, 41.5,
and 45.7, respectively. The formation of the thiadiazole derivatives has been
identified from the HMBC spectrum of 25, which showed a 2J C,H correlation
2
between CH2SPh at δH 4.27 and C-6 at δC 174.7 in comparison for a J C,H
correlation in 23 between C O (C-6) and SCH2. A plausible mechanism
for formation of 25–27 likely involves the sulphur participation to form the
episulphonium ion 24 (Scheme 2).

Microwave-Assisted Synthesis of Novel Acyclic C-Nucleosides
473
SCHEME 2 Reagents and conditions (i) BrCH2CO2H, DMF, 45 min, MWI; (ii) RSNa or RSH, Et3N, reflux,
CH2Cl2, (III) 80% HOAc, 80◦C, 12 h.
Acid hydrolysis of 25–27 with 80% HOAc at 80◦C gave the free nucleo-
sides 28–30 in 85, 83, and 90% yield, respectively. Similary, the structures of
1
28–30 were assigned from the H-, 13C-NMR and mass spectra, which their
sugar protons and carbons were almost identical for those of 13–20.
IN VITRO ANTI-HIV-ASSAY
All the new synthesized compounds were evaluated for their in vitro
anti-HIV activity using the MT-4/MTT assay.[29] Of the compounds tested,
only compound 6 showed any antiviral activity against HIV-2. Compound
6 showed an EC50 of 17.30 µg/mL and a CC50 of 97.17
18.09 µg/mL,
resulting in a selectivity index of 5. Based on the chemical structure and the
fact that compound 6 inhibits HIV-2 in comparison to 3–5 and 7–30, it can

474
Y. A. Al-Soud et al.
be concluded that the 3,4-dichlorophenyl residue play a major role in the
antiviral activity in such molecules.
EXPERIMENTAL
Microwave supported reactions were performed in a SmithSynthesizer
(Personal Chemistry AB, monomode microwave cavity at 2.45 GHz, tem-
perature control by automated adjustment of irradiation power in a range
from 0 to 300 W) in Biotage microwave reaction vials (2–5 mL) with
Teflon septum and an aluminum crimp top. Melting points are uncorrected
and were measured on a Bu¨chi melting point apparatus B-545 (Bu¨chi
Labortechnik AG, Switzerland). Microanalytical data were obtained with a
Vario, Elementar apparatus (Shimadzu, Japan). NMR spectra were recorded
on 300 and 600 MHz (1H) and at 62.9 MHz (13C) spectrometers (Bruker,
Germany) with TMS as internal standard and on δ scale in ppm. Heteronu-
clear assignments were verified by 1H-13C HMBC experiment. Mass spectra
were recorded at 70 eV on EI and FAB mass spectra were measured on a
MAT 8200 spectrometer (Finnigana MAT, USA) using 3-nitrobenzyl alcohol
(NBOH) or glycerol as matrices. Some molecular ions were detected by
doping the sample with Na+ ion.
4-Amino-3-(1,2-O-isopropylidene-D-ribo-tetritol-1-yl)-5-mercapto-1,2,4-triazole
(3). A mixture of thiocarbohydrazide (94 mg, 0.50 mmol) and 2 (53 mg,
0.50 mmol) in pyridine (5 mL) was sealed with a Teflon septum and an
aluminum crimp top in a glass vial (Biotage microwave reaction vial 2–5
mL). The vessel was then heated to 120◦C under microwave irradiation
using the SmithSynthesizer. After 15 minutes the vial was cooled to rroom
temperature by gas jet cooling. The solution was evaporated to dryness
and the residue was washed with EtOH (4×15 mL). The white precipitate
was recrystallized from EtOH to give 2 (120 mg, 87%), m.p. 121–123◦C.
1H NMR (CDCl3): δ 4.83 (d., 1H, J 1 ,2 = 5.5 Hz, H-1ꢁ); 4.77 (dd, 1H, J =
ꢁ
ꢁ
2.7 Hz, H-2ꢁ); 4.62 (t, 1H, J 3 ,4 b = 2.7 Hz, H-3ꢁ); 3.99 (dd, J 3 ,4 a = 2.2 Hz,
ꢁ
ꢁ
ꢁ
ꢁ
H-4ꢁa); 3.80 (dd, 1H, J 4 a,4 b = 12.0 Hz, H-4ꢁb); 2.56 (br s, 2H, OH); 1.47,
1.38 (2 × s, 6H, CMe2). 13C NMR (DMSO-d6): δ 182.0 (C S); 174.2 (C N);
111.5 (CMe2); 82.1 (C-2ꢁ); 78.0 (C-1ꢁ); 74.9 (C-3ꢁ); 60.3 (C-4ꢁ); 26.4, 25.0
(CMe2). Anal. calc. for C9H16N4O4S (276.31): C, 39.12; H, 5.84; N, 20.28.
Found; C, 38.89; H, 5.73; N, 20.06. MS: m/z (FAB) 277 (M+H)+.
ꢁ
ꢁ
N4-Amino-5-(D-ribo-tetritol-1-yl)-1,2,4-triazole-3-thiol (4). A solution of 3
(0.25 mmol) in 80% HOAc (10 mL) was stirred at 80◦C for 12 hours. The
solution was evaporated to dryness and the residue was co-evaporated with
EtOH (4×20 mL) and the residue was extracted between water (15 mL) and
diethyl ether (3×15 mL). The aq. layer was evaporated to dryness to give 4
(110 mg, 73%); m.p. 121–123◦C. 1H NMR (DMSO-d6): δ 12.89 (s, 1H, SH);
5.82 (s, 2H, NH2); 5.60 (br s, 4H, OH); 4.40 (d, 1H, J 1 ,2 = 5.4 Hz, H-1ꢁ);
ꢁ
ꢁ

Microwave-Assisted Synthesis of Novel Acyclic C-Nucleosides
475
4.22 (dd, 1H, J 2 ,3 = 2.7 Hz, H-2ꢁ); 4.12 (t, 1H, J 3 ,4 b = 2.7 Hz, H-3ꢁ); 3.56
(m, 2H, H-4ꢁa, H-4ꢁb). 13C NMR (DMSO-d6): δ 176.3 (C-SH); 174.2 (C N);
85.3 (C-2ꢁ); 69.3 (C-3ꢁ); 68.6 (C-1ꢁ); 60.4 (C-4ꢁ). Anal. calc. for C6H12N4O4S
(236.25): C, 30.50; H, 5.12; N, 23.72. Found; C, 30.30; H, 5.01; N, 23.48. MS:
m/z (FAB) 237 (M+H)+.
ꢁ
ꢁ
ꢁ
ꢁ
6-Alkyl/aryl-3-(1,2-O-isopropylidene-D-ribo-tetritol-1-yl)[1,2,4]triazolo[3,4-
b][1,3,4]thia-diazoles (5–12). A mixture of 3 (100 mg, 0.36 mmol) and
the appropriate aryl or alkyl benzoic acid (0.40 mmol) in DMF (5 mL)
was sealed with a Teflon septum and an aluminum crimp top in a glass
vial (Biotage microwave reaction vial 2–5 mL). The vessel was then heated
to 120◦C under microwave irradiation using the SmithSynthesizer. After
45 minutes, the vial was cooled to room temperature by gas jet cooling.
The solution was evaporated to dryness and the residue was partitioned
between water (15 mL) and EtOAc (15 mL). The organic layer was dried
(Na2SO4), filtered and evaporated to dryness to give a white precipitate,
which recrystallized from EtOH or EtOAc to give the desired product.
6-(4-Chlorophenyl)-3-(1,2-O-isopropylidene-D-ribo-tetritol-1-yl)[1,2,4]triazolo
[3,4-b][1,3,4] thiadiazole (5). From 2-chlorobenzoic acid (62 mg). Yield:
1
80 mg (56%); m.p. 121–123◦C. H NMR (CDCl3): δ 7.99 (dd, 1H, J =
ꢁ
ꢁ
6.8 Hz, 1.6 Hz, ArH); 7.49–7.34 (m, 3H, ArH); 4.84 (d, 1H, J 1 ,2 = 5.6
Hz, H-1ꢁ); 4.78 (dd, 1H, J 2 ,3 = 2.2 Hz, H-2ꢁ); 4.63 (t, 1H, J 3 ,4 b = 2.2 Hz,
ꢁ
ꢁ
ꢁ
ꢁ
H-3ꢁ); 3.99 (dd, 1H, J 3 ,4 a = 4.8 Hz, H-4ꢁa); 3.81 (dd, 1H, J 4 a,4 b = 12.1
Hz, H-4ꢁb); 1.48, 1.38 (2 × s, 6H, CMe2). 13C NMR (CDCl3): δ 174.2 (C-6);
163.4 (C-3); 141.4 (C-8); 133.3, 132.3, 131.4, 126.4 (Ar-C); 113.2 (CMe2);
82.7 (C-2ꢁ); 78.0 (C-1ꢁ); 75.7 (C-3ꢁ); 62.0 (C-4ꢁ); 26.7, 25.5 (CMe2). Anal.
calc. for C16H17ClN4O4S (396.85): C, 48.42; H, 4.32; N, 14.12. Found; C,
48.59; H, 4.25; N, 14.06. MS: m/z (FAB) 396/398 (M+2)+.
ꢁ
ꢁ
ꢁ
ꢁ
6-(3,4-Dichlorophenyl)-3-(1,2-O-isopropylidene-D-ribo-tetritol-1-yl)-7H-1,2,4-
triazolo [3,4-b][1,3,4] thiadiazole (6). From 3,4-dichlorobenzoic acid (48
mg). Yield: 96 mg (88%); m.p. 116–119◦C. 1H NMR (CDCl3): δ 8.17 (d, 1H,
J = 2.0 Hz, ArH); 7.93 (dd, 1H, J = 6.3 Hz, 2.0 Hz, ArH); 7.56 (d, 1H, J =
6.3 Hz, ArH); 4.81 (d., 1H, J 1 ,2 = 5.4 Hz, H-1ꢁ); 4.77 (dd, 1H, J 2 ,3 = 2.3
ꢁ
ꢁ
ꢁ
ꢁ
Hz, H-2ꢁ); 4.63 (t, 1H, J 3 ,4 b = 2.3 Hz, H-3ꢁ); 3.99 (dd, 1H, J 3 ,4 a = 4.6 Hz,
ꢁ
ꢁ
ꢁ
ꢁ
H-4ꢁa); 3.81 (dd, 1H, J 4 a,4 b = 12.2 Hz, H-4ꢁb); 1.47, 1.38 (2 × s, 6H, CMe2).
13C NMR (CDCl3): δ 174.2 (C-6); 163.5 (C-3); 141.5 (C-8); 132.1, 130.7,
129.1 (Ar-C); 113.2 (CMe2); 82.6 (C-2ꢁ); 78.2 (C-1ꢁ); 75.7 (C-3ꢁ); 62.1 (C-4ꢁ);
26.7, 25.5 (CMe2). Anal. calc. for C16H16 Cl2N4O4S (431.29): C, 44.56; H,
3.74; N, 12.99. Found; C, 44.32; H, 3.59; N, 12.71. MS: m/z (FAB) 431/433
(M+2)+.
ꢁ
ꢁ
6-(3-Aminophenyl)-3-(1ꢁ,2ꢁ-O-isopropylidene-D-ribo-tetritol-1-yl)-7H-1,2,4-
triazolo[3,4-b][1,3,4] thiadiazole (7). From 3-aminobenzoic acid (34 mg).
1
Yield: 84 mg (88%); m.p. 106–108◦C. H NMR (CDCl3): δ 8.07 (br s, 2H,
ꢁ
ꢁ
NH2); 7.41, 7.34, 7.18, 6.86 (m, 4H, ArH); 4.78 (d., 1H, J 1 ,2 = 5.6 Hz,
H-1ꢁ); 4.71 (dd, 1H, J 2 ,3 = 2.3 Hz, H-2ꢁ); 4.56 (t, 1H, J 3 ,4 b = 2.3 Hz, H-3ꢁ);
ꢁ
ꢁ
ꢁ
ꢁ

476
Y. A. Al-Soud et al.
3.93 (dd, 1H, J 3 ,4 a = 4.6 Hz, H-4ꢁa); 3.74 (dd, 1H, J 4 a,4 b = 12.3 Hz, H-4ꢁb);
1.41, 1.31 (2 × s, 6H, CMe2). 13C NMR (CDCl3): δ 174.8 (C-6); 170.1 (C-3);
146.4 (C-8); 136.4, 130.6, 130.3, 120.4, 116.2 (Ar-C); 113.2 (CMe2); 82.7
(C-2ꢁ); 78.2 (C-1ꢁ); 75.6 (C-3ꢁ); 62.0 (C-4ꢁ); 26.7, 25.5 (CMe2). Anal. calc.
for C16H19N5O4S (377.42): C, 50.92; H, 5.07; N, 18.56. Found; C, 50.71; H,
4.94; N, 18.37. MS: m/z (FAB) 378 (M+H)+.
ꢁ
ꢁ
ꢁ
ꢁ
6-(4-Aminophenyl)-3-(1,2-O-isopropylidene-D-ribo-tetritol-1-yl)-7H-1,2,4-
triazolo [3,4-b][1,3,4] thiadiazole (8). From 4-aminobenzoic acid (34 mg).
Yield: 80 mg (84%); m.p. 155–158◦C. 1H NMR (CDCl3): δ 7.94 (d, 2H, J =
14.1 Hz, NH2); 7.84 (dd, 2H, J = 8.8 Hz, 2.2 Hz, ArH); 6.59 (dd, 2H, J =
8.8 Hz, 2.2 Hz, ArH); 4.79 (d, 1H, J 1 ,2 = 5.6 Hz, H-1ꢁ); 4.72 (dd, 1H, J 2 ,3
ꢁ
ꢁ
ꢁ
ꢁ
= 1.8 Hz, H-2ꢁ); 4.56 (t, 1H, J 3 ,4 b = 1.8 Hz, H-3ꢁ); 3.90 (dd, 1H, J 3 ,4 a = 4.2
ꢁ
ꢁ
ꢁ
ꢁ
Hz, H-4ꢁa); 3.74 (dd, 1H, J 4 a,4 b = 12.3 Hz, H-4ꢁb); 1.41, 1.31 (2 × s, 6H,
CMe2). 13C NMR (CDCl3): δ 174.9 (C-6); 162.8 (C-3); 141.4 (C-8); 132.2,
118.7, 113.7 (Ar-C); 113.0 (CMe2); 82.7 (C-2ꢁ); 78.3 (C-1ꢁ); 75.6 (C-3ꢁ); 61.8
(C-4ꢁ); 26.7, 25.4 (CMe2). Anal. calc. for C16H19N5O4S (377.42): C, 50.92;
H, 5.07; N, 18.56. Found; C, 50.68; H, 4.97; N, 18.54. MS: m/z (FAB) 378
(M+H)+.
ꢁ
ꢁ
3-(1,2-O-Isopropylidene-D-ribo-tetritol-1-yl)-6-(thiophen-2-yl)-7H-1,2,4-
triazolo[3,4-b][1,3,4] thiadiazole (9). From thiophene-2-carboxylic acid
1
(32 mg). Yield: 90 mg (93%); m.p. 102–104◦C. H NMR (CDCl3): δ 7.81
(dd, 1H, J = 3.6 Hz, 1.8 Hz, thiophen-H); 7.56 (dd, 1H, J = 4.8 Hz, 1.8 Hz,
thiophen-H); 7.06 (dd, 1H, J = 3.6 Hz, 4.8 Hz, thiophen-H); 4.78 (d., 1H,
J 1 ,2 = 5.5 Hz, H-1ꢁ); 4.72 (dd, 1H, J 2 ,3 = 2.3 Hz, H-2ꢁ); 4.57 (t, 1H, J 3 ,4 b
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
= 2.3 Hz, H-3ꢁ); 3.92 (dd, 1H, J 3 ,4 a = 4.5 Hz, H-4ꢁa); 3.74 (dd, 1H, J 4 a,4 b
= 12.2 Hz, H-4ꢁb); 2.56 (br s, 2H, OH); 1.40, 1.31 (2 × s, 6H, CMe2). 13C
NMR (CDCl3): δ 174.9 (C-6); 166.5 (C-3); 141.4 (C-8); 134.4, 133.6, 133.1,
127.9 (thiophen-C); 113.1 (CMe2); 82.8 (C-2ꢁ); 78.3 (C-1ꢁ); 75.6 (C-3ꢁ); 61.9
(C-4ꢁ); 26.8, 25.4 (CMe2). Anal. calc. for C14H16N4O4S2 (368.43): C, 45.64;
H, 4.38; N, 15.21. Found; C, 45.39; H, 4.21; N, 14.98. MS: m/z (FAB) 369
(M+H)+.
ꢁ
ꢁ
ꢁ
ꢁ
6-(Adamantan-1-yl)-3-(1,2-O-isopropylidene-D-ribo-tetritol-1-yl)-7H-1,2,4-
triazolo[3,4-b][1,3,4]thiadiazole (10). From 1-adamantan-carboxylic acid
(45 mg). Yield: 100 mg (94%); semi-solid. 1H NMR (CDCl3): δ 4.83 (d, 1H,
J 1 ,2 = 5.7 Hz, H-1ꢁ); 4.78 (dd, 1H, J 2 ,3 = 2.0 Hz, H-2ꢁ); 4.63 (t, 1H, J 3 ,4 b
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
= 2.0 Hz, H-3ꢁ); 3.99 (dd, 1H, J 3 ,4 a = 4.4 Hz, H-4ꢁa); 3.81 (dd, 1H, J 4 a,4 b
= 12.3 Hz, H-4ꢁb); 2.02 (m, 2H, adamant-H), 1.90 (m, 4H, adamant-H);
1.71 (m, 4H, adamant-H); 1.47, 1.38 (2 × s, 6H, CMe2). 13C NMR (CDCl3):
δ 183.4 (C-6); 174.9 (C-3); 151.2 (C-8); 113.1 (CMe2); 82.7 (C-2ꢁ); 78.2
(C-1ꢁ); 75.6 (C-3ꢁ); 61.9 (C-4ꢁ); 40.4, 38.6, 36.4, 27.8 (adamant-C), 26.7, 25.4
(CMe2). Anal. calc. for C20H28N4O4S (420.53): C, 57.12; H, 6.71; N, 13.32.
Found; C, 56.89; H, 6.58; N, 13.19. MS: m/z (FAB) 421 (M+H)+.
ꢁ
ꢁ
ꢁ
ꢁ
6-(Coumarin-3-yl)-3-(1,2-O-isopropylidene-D-ribo-tetritol-1-yl)-7H-1,2,4-
triazolo[3,4-b][1,3,4]thiadiazole (11). From coumarin-3-carboxylic acid (47

Microwave-Assisted Synthesis of Novel Acyclic C-Nucleosides
477
mg). Yield: 94 mg (83%); m.p. 101–105◦C. 1H NMR (CDCl3): δ 8.00 (s, 1H,
coumar-H-4); 7.71 (d, 1H, J = 7.6 Hz, coumar-H-5); 7.50 (t, 1H, J = 7.6
Hz, coumar-H-7); 7.35 (d, 1H, J = 7.7 Hz, coumar-H-8); 7.27 (t, 1H, J =
7.6 Hz, coumar-H-6); 4.82 (d, 1H, J 1 ,2 = 5.6 Hz, H-1ꢁ); 4.78 (dd, 1H, J 2 ,3
ꢁ
ꢁ
ꢁ
ꢁ
= 2.2 Hz, H-2ꢁ); 4.61 (t, 1H, J 3 ,4 b = 2.2 Hz, H-3ꢁ); 3.98 (dd, 1H, J 3 ,4 a = 4.2
ꢁ
ꢁ
ꢁ
ꢁ
Hz, H-4ꢁa); 3.79 (dd, 1H, J 4 a,4 b = 12.0 Hz, H-4ꢁb); 1.47, 1.38 (2 × s, 6H,
CMe2). 13C NMR (CDCl3): δ 174.7 (C-6); 162.7 (coumar-C-2); 160.0 (C-3);
154.1 (C-8); 150.1 (coumar-C-8a); 143.4 (coumar-C-4); 131.8 (coumar-C-3);
129.8 (coumar-C-7); 127.8 (coumar-C-5); 124.4 (coumar-C-6); 120.2
(coumar-C-8); 118.8 (coumar-C-4a); 113.1 (CMe2); 82.6 (C-2ꢁ); 78.3 (C-1ꢁ);
75.6 (C-3ꢁ); 62.0 (C-4ꢁ); 26.7, 25.5 (CMe2). Anal. calc. for C19H20N4O6S
(432.45): C, 52.77; H, 4.66; N, 12.96. Found; C, 52.53; H, 4.54; N, 12.72.
MS: m/z (FAB) 433 (M+H)+.
ꢁ
ꢁ
6-(3-Dimethylaminophenyl)-3-(1,2-O-isopropylidene-D-ribo-tetritol-1-yl)-7H-
1,2,4-triazolo[3,4-b][1,3,4]thiadiazole
(12). From
3-(dimethylamino)
1
benzoic acid (41 mg). Yield: 83 mg (81%); m.p. 110–112◦C. H NMR
(CDCl3): δ 7.42–7.39 (m, 2H, ArH); 7.26 (t, 1H, J = 8.1 Hz, ArH); 6.91
ꢁ
ꢁ
(ddd, 1H, J = 8.3 Hz, 2.7 Hz, 1.0 Hz, ArH); 4.78 (d, 1H, J 1 ,2 = 5.8 Hz,
H-1ꢁ); 4.72 (dd, 1H, J 2 ,3 = 2.1 Hz, H-2ꢁ); 4.57 (t, 1H, J 3 ,4 b = 2.1 Hz, H-3ꢁ);
ꢁ
ꢁ
ꢁ
ꢁ
3.94 (dd, 1H, J 3 ,4 a = 4.1 Hz, H-4ꢁa); 3.94 (dd, 1H, J 4 a,4 b = 12.2 Hz, H-4ꢁb);
2.95 (2 × s, 6H, NMe2); 1.421, 1.33 (2 × s, 6H, CMe2). 13C NMR (CDCl3):
δ 174.1 (C-6); 171.8 (C-3); 150.5 (C-8); 130.0, 129.1, 118.3, 117.6 (Ar-C);
113.2 (CMe2); 82.6 (C-2ꢁ); 78.2 (C-1ꢁ); 75.7 (C-3ꢁ); 62.1 (C-4ꢁ); 52.1 (NMe2),
26.7, 25.5 (CMe2). Anal. calc. for C18H23N5O4S (405.47): C, 53.32; H, 5.72;
N, 17.27. Found; C, 53.01; H, 5.59; N, 16.95. MS: m/z (FAB) 406 (M+H)+.
ꢁ
ꢁ
ꢁ
ꢁ
6-Alkyl/aryl-3-(D-ribo-tetritol-1-yl)-7H-1,2,4-triazolo[3,4-b][1,3,4]
thiadiazoles (13–20)
These compounds were prepared from 5–12 (0.25 mmol), as oily or
solid product, by following the procedure used for the preparation of 4.
6-(2-Chlorophenyl)-3-(D-ribo-tetritol-1-yl)-[1,2,4-triazolo][3,4-b][1,3,4] thiadi-
azole (13). From 5 (75 mg). Yield: 50 mg (74%); m.p. 122–124◦C. 1H NMR
(DMSO-d6): δ 7.97 (dd, 1H, J = 7.3 Hz, 1,7 Hz, ArH); 7.61–7.20 (m, 3H,
Ar-H); 4.64 (br s, 4H, OH); 4.39 (d, 1H, J 1 ,2 = 5.0 Hz, H-1ꢁ); 4.21 (t,
ꢁ
ꢁ
1H, J 2 ,3 = 5.0 Hz, H-2ꢁ); 4.12 (m, 1H, H-3ꢁ); 3.57 (m, 2H, H-4ꢁa, H-4ꢁb).
13C NMR (DMSO-d6): δ 176.2 (C-6); 166.4 (C-3); 143.7 (C-8); 132.2, 131.6,
131.3, 130.4, 126.4 (Ar-C); 85.2 (C-2ꢁ); 69.2 (C-3ꢁ); 68.5 (C-1ꢁ). Anal. calc.
for C13H13ClN4O4S (356.78): C, 43.76; H, 3.67; N, 15.70. Found; C, 43.48;
H, 3.56; N, 15.51. MS: m/z (FAB) 356/358 (M+2)+.
ꢁ
ꢁ
6-(3,4-Dichlorophenyl)-3-(D-ribo-tetritol-1-yl)-[1,2,4-triazolo][3,4-b][1,3,4]
1
thiadiazole (14). From 6 (75 mg). Yield: 80 mg (73%); m.p. 91–94◦C. H
NMR (DMSO-d6): δ 8.05 (d, 1H, J = 2.0 Hz, ArH); 7.86 (dd, 1H, J = 6.5
Hz, 2.0 Hz, Ar-H); 7.76 (d, 1H, J = 6.5 Hz, Ar-H); 5.95 (br s, 4H, OH); 4.41

478
Y. A. Al-Soud et al.
(d, 1H, J 1 ,2 = 5.4 Hz, H-1ꢁ); 4.21 (t, 1H, J 2 ,3 = 5.4 Hz, H-2ꢁ); 4.12 (m,
1H, H-3ꢁ); 3.56 (m, 2H, H-4ꢁa, H-4ꢁb). 13C NMR (DMSO-d6): δ 176.5 (C-6);
165.3 (C-3); 156.1 (C-8); 131.4, 131.0, 130.8, 129.2 (Ar-C); 85.3 (C-2ꢁ); 69.3
(C-3ꢁ); 68.6 (C-1ꢁ); 60.4 (C-4ꢁ). Anal. calc. for C13H12Cl2N4O4S (391.23): C,
39.91; H, 3.09; N, 14.32. Found; C, 39.68; H, 2.98; N, 14.05. MS: m/z (FAB)
413/415 (M+Na)+/M+Na+2)+.
ꢁ
ꢁ
ꢁ
ꢁ
6-(3-Aminophenyl)-3-(D-ribo-tetritol-1-yl)-[1,2,4-triazolo][3,4-b][1,3,4]
thiadiazole (15). From 7 (94 mg). Yield: 72 mg (85%); semi-solid. 1H NMR
(DMSO-d6): δ 7.93 (m, 2H, ArH); 7.61 (m, 2H, Ar-H); 5.52 (br s, 4H, OH);
4.42 (d, 1H, J 1 ,2 = 5.4 Hz, H-1ꢁ); 4.23 (t, 1H, J 2 ,3 = 5.4 Hz, H-2ꢁ); 4.13 (m,
1H, H-3ꢁ); 3.18 (m, 2H, H-4ꢁa, H-4ꢁb). 13C NMR (DMSO-d6): δ 176.2 (C-6);
166.1 (C-3); 158.0 (C-8); 133.4, 132.0, 129.9, 127.7, 126.8, 123.2 (Ar-C);
85.2 (C-2ꢁ); 69.2 (C-3ꢁ); 68.4 (C-1ꢁ); 60.3 (C-4ꢁ). Anal. calc. for C13H15N5O4S
(337.35): C, 46.28; H, 4.48; N, 20.76. Found; C, 45.96; H, 4.39; N, 20.54.
MS: m/z (FAB) 338 (M+H)+.
ꢁ
ꢁ
ꢁ
ꢁ
6-(4-Aminophenyl)-3-(D-ribo-tetritol-1-yl)-[1,2,4-triazolo][3,4-b][1,3,4]
thiadiazole (16). From 8 (94 mg). Yield: 66 mg (78%); m.p. 155–158◦C.
1H NMR (DMSO-d6): δ 8.96 (br s, 2H, NH2); 7.95 (dd, 2H, J = 7.0 Hz, 1.3
Hz, ArH); 7.32 (dd, 2H, J = 7.0 Hz, 1.3 Hz, Ar-H), 5.30 (br s, 4H, OH);
4.44 (d, 1H, J 1 ,2 = 5.3 Hz, H-1ꢁ); 4.34 (t, 1H, J 2 ,3 = 5.3 Hz, H-2ꢁ); 4.15 (d,
1H, J = 5.3 Hz, H-3ꢁ); 3.17 (m, 2H, H-4ꢁa, H-4ꢁb). 13C NMR (DMSO-d6):
δ 176.6 (C-6); 166.7 (C-3); 142.7 (C-8); 130.9, 127.5, 124.2, 121.3 (Ar-C);
85.4 (C-2ꢁ); 69.4 (C-3ꢁ); 68.7 (C-1ꢁ); 60.5 (C-4ꢁ). Anal. calc. for C13H15N5O4S
(337.35): C, 46.28; H, 4.48; N, 20.76. Found; C, 46.02; H, 4.37; N, 20.50.
MS: m/z (FAB) 338 (M+H)+.
ꢁ
ꢁ
ꢁ
ꢁ
3-(D-Ribo-tetritol-1-yl)-6-(thiophen-2-yl)-[1,2,4-triazolo][3,4-b][1,3,4]
1
thiadiazole (17). From 9 (92 mg). Yield: 59 mg (72%); semi-solid. H
NMR (DMSO-d6): δ 7.89 (dd, 1H, J = 3.5 Hz, 1.7 Hz, thiophene-H);
7.73 (dd, 1H, J = 4.5 Hz, 1.7 Hz, thiophene-H), 7.19 (dd, 1H, J = 3.5
ꢁ
ꢁ
Hz, 4.8 Hz, thiophene-H); 4.89 (br s., 4H, OH); 4.20 (d, 1H, J 1 ,2 = 5.4
Hz, H-1ꢁ); 4.22 (d, 1H, J 2 ,3 = 5.4 Hz, H-2ꢁ); 4.12 (t, 1H, J = 3.1 Hz,
H-3ꢁ); 3.57 (m, 2H, H-4ꢁa, H-4ꢁb). 13C NMR (DMSO-d6): δ 176.5 (C-6);
162.8 (C-3; 148.5 (C-8); 128.3, 127.5, 125.3 (Ar-C); 85.4 (C-2ꢁ); 68.7 (C-3ꢁ);
69.4 (C-1ꢁ); 60.5 (C-4ꢁ). Anal. calc. for C11H12N4O4S2 (328.37): C, 40.23;
H, 3.68; N, 17.06. Found; C, 39. 94; H, 3.58; N, 16.86. MS: m/z (FAB)
329 (M+H)+.
ꢁ
ꢁ
6-(Adamantan-2-yl)-3-(D-ribo-tetritol-1-yl)-[1,2,4-triazolo][3,4-b][1,3,4]
thiadiazole (18). From 10 (105 mg). Yield: 63 mg (66%); m.p. 75–77◦C. 1H
NMR (DMSO-d6): δ 5.21 (br s, 4H, OH); 4.97 (d, 1H, J 1 ,2 = 5.5 Hz, H-1ꢁ);
ꢁ
ꢁ
4.78 (t, 1H, J 2 ,3 = 3.2 Hz, H-2ꢁ); 4.63 (t, 1H, J 3 ,4 b = 5.4 Hz, H-3ꢁ); 4.12
(m, 2H, H-4ꢁa, H-4ꢁb); 2.33 (m, 2H, adamant-H), 2.20 (m, 4H, adamant-H);
1.80 (m, 4H, adamant-H). 13C NMR (DMSO-d6): δ 167.2 (C-6); 163.5 (C-3);
154.2 (C-8); 85.2 (C-2ꢁ); 69.3 (C-3ꢁ); 68.4 (C-1ꢁ); 60.4 (C-4ꢁ); 37.9, 36.0, 31.2,
ꢁ
ꢁ
ꢁ
ꢁ

Microwave-Assisted Synthesis of Novel Acyclic C-Nucleosides
479
27.4 (adamant-C). Anal. calc. for C17H24N4O4S (380.46): C, 53.67; H, 6.36;
N, 14.73. Found; C, 53.43; H, 6.29; N, 14.52. MS: m/z (FAB) 381 (M+H)+.
6-(Coumarin-3-yl)-3-(D-ribo-tetritol-1-yl)-[1,2,4-triazolo][3,4-b][1,3,4]
thiadiazole (19). From 11 (108 mg). Yield: 80 mg (82%); semi-solid.
1H NMR (DMSO-d6): δ 8.10 (s, 1H, coumarin-H-4); 7.74 (d, 1H, J = 7.2 Hz,
coumarin-H-5); 7.59 (t, 1H, J = 7.1 Hz, coumarin-H-7); 7.40 (d, 1H, J = 7.8
ꢁ
ꢁ
Hz, coumarin-H-8); 7.35 (t, 1H, J = 7.1 Hz, coumarin-H-6); 4.43 (d, 1H, J 1 ,2
= 5.4 Hz, H-1ꢁ); 4.78 (d, 1H, J 2 ,3 = 5.4 Hz, H-2ꢁ); 4.61 (t, 1H, J 3 ,4 b = 2.7
Hz, H-3ꢁ); 3.57 (m, 2H, H-4ꢁa, H-4ꢁb). 13C NMR (DMSO-d6): δ 176.2 (C-6);
161.5 (coumarin-C-2); 158.0 (C-3); 148.2 (C-8); 150.0 (coumarin-C-8a);
145.6 (coumarin-C-4); 131.8 (coumarin-C-3); 128.1 (coumarin-C-7); 126.4
(coumarin-C-5); 125.0 (coumarin-C-6); 121.9 (coumarin-C-8, C-4a); 85.2
(C-2ꢁ); 69.1 (C-1ꢁ); 68.5 (C-3ꢁ); 60.3 (C-4ꢁ). Anal. calc. for C16H14N4O6S
(390.37): C, 49.23; H, 3.61; N, 14.35. Found; C, 48.97; H, 3.50; N, 14.07.
MS: m/z (FAB) 412/414 (M+Na)+.
ꢁ
ꢁ
ꢁ
ꢁ
6-(3-Dimethylaminophenyl)-3-(D-ribo-tetritol-1-yl)[1,2,4]-triazolo[3,4-b][1,3,4
1
]thiadiazole (20). From 12 (101 mg). Yield: 76 mg (83%); oil. H NMR
(DMSO-d6): δ 8.10–7.57 (m, 4H, ArH); 5.82 (br s, 4H, OH); 4.41 (d., 1H,
J 1 ,2 = 5.4 Hz, H-1ꢁ); 4.22 (d, 1H, J 2 ,3 = 5.4 Hz, H-2ꢁ); 4.12 (t, 1H, J 3 ,4 b
=ꢁ 3.3 Hz, H-3ꢁ); 3.46 (m, 2H, H-4ꢁa, H-4ꢁb); 3.09, 3.07 (2 × s, 6H, NMe2).
13C NMR (DMSO-d6): δ 176.4 (C-6); 166.4 (C-3); 151.9 (C-8); 132.2, 130.8,
130.0 (Ar-C); 85.3 (C-2ꢁ); 69.3 (C-3ꢁ); 68.6 (C-1ꢁ); 60.4 (C-4ꢁ); 52.3 (NMe2).
MS: m/z (FAB) 366 (M+H)+.
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
1ꢁ,2ꢁ,3ꢁ,4ꢁ-Tetra-O-acetyl-1-(6-(3,4-dichlorophenyl)-3-(D-ribo-
tetritol-1-yl)[1,2,4]-triazolo[3,4-b][1,3,4]thiadiazole (21)
To a solution of 14 (60 mg, 0.15 mmol) in pyridine (5.0 mL) was added
acetic anhydride (2.0 mL) and kept for 18 h at 23◦C. The mixture was
evaporated to dryness and the residue was co-evaporated with EtOH (4 ×
15 mL). The residue was purified on a short column of silica gel (using
1
CHCl3-MeOH 95:5, as eluent) to give 21 (70 mg, 83%); m.p. 71–74◦C H
NMR (600 MHz, CDCl3): δ 8.10 (br s, 1H, ArHf); 7.85 (d, 1H, J = 8.2 Hz,
Ar-Hb); 7.47 (d, 1H, J = 8.2 Hz, Ar-Hc); 5.73 (d, 1H, J 1 ,2 = 6.0 Hz, H-1ꢁ);
ꢁ
ꢁ
5.46 (d, 1H, J 2 ,3 = 6.0 Hz, H-2ꢁ); 4.73 (t, 1H, J 2 ,3 = 3.0 Hz, H-3ꢁ); 4.37
ꢁ
ꢁ
ꢁ
ꢁ
(dd, 1H, J 3 ,4 a = 3.1 Hz, H-4ꢁa); 4.33 (dd, 1H, J 3 ,4 a = 3.0 Hz, J 4 a,4 b = 12.2
Hz, H-4ꢁb); 2.25, 2.13, 2.12, 2.10 (4xs, 12H, 4 x OAc). 13C NMR (DMSO-d6):
δ 170.7 (C O); 170.2 (C-6); 169.8 (C-3); 156.7 (C-8); 134.1 (Ar-Cd); 133.1
(Ar-Ce),; 132.9 (Ar-Cb); 130.6 (Ar-Cf); 129.0 (Ar-Cc, Ar-Ca); 79.9 (C-2ꢁ); 69.9
(C-1ꢁ); 67.3 (C-3ꢁ); 63.8 (C-4ꢁ). Anal. calc. for C21H20Cl2N4O8S (559.38): C,
45.09; H, 3.60; N, 10.02. Found; C, 44.81; H, 3.51; N, 9.78. MS: m/z (FAB)
558/560 M+/(M+2)+.
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ

480
Y. A. Al-Soud et al.
3-(1,2-O-Ispropylidene-D-ribo-tetritol-1-yl)-5H-[1,2,4]-triazolo[3,4-
b][1,3,4]thiadiazin-6-one (23)
This compound was prepared from compound 3 (70 mg, 0.25 mmmol)
and 2-bromoacetic acid (35 mg, 0.25 mmol), by the procedure of prepara-
tion of 5–12. Yield: 54 mg (57%); m.p. 115–116◦C. 1H NMR (CDCl3): δ 4.78
(d, 1H, J 1 ,2 = 5.6 Hz, H-1ꢁ); 4.72 (d, 1H, J 2 ,3 = 5.6 Hz, H-2ꢁ); 4.56 (t, 1H,
ꢁ
ꢁ
ꢁ
ꢁ
J 3 ,4 b = 2.0 Hz, H-3ꢁ); 3.90 (dd, 1H, J 3 ,4 a = 2.3 Hz, H-4ꢁa); 3.73 (dd, 1H,
ꢁ
ꢁ
ꢁ
ꢁ
J 4 a,4 b = 12.3 Hz, H-4ꢁb); 2.81 (s., 2H, SCH2); 1.40, 1.31 (2 × s, 6H, CMe2).
13C NMR (CDCl3): δ 175.1 (C O); 163.0 (C-3); 149.9 (C-9); 113.0 (CMe2);
82.8 (C-2ꢁ); 78.3 (C-1ꢁ); 75.7 (C-3ꢁ); 61.7
ꢁ
ꢁ
(C-4ꢁ); 36.7 (SCH2); 26.6, 25.4 (CMe2). Anal. calc. for C11H16N4O5S
(316.33): C, 41.77; H, 5.10; N, 17.71. Found; C, 41.52; H, 5.01; N, 17.50.
MS: m/z (FAB) 317 (M+H)+.
6-(Alkyl/aryl-thiomethyl)-3-(1,2-O-isopropylidene-D-ribo-tetritol-1-
yl)[1,2,4]triazolo
[3,4-b][1,3,4]thiadiazoles (25–27)
To a stirred solution of 23 (95 mg, 0.25 mmol) in CH2Cl2 were added
aryl mercaptans (0.25 mmol) and refluxed for 5 hours. After cooling, the
solution was evaporated to dryness and the residue was purified on short
SiO2 column, using CH2Cl2-MeOH (95:5) as eluent, giving 25–27.
3-(1,2-O-Isopropylidene-D-ribo-tetritol-1-yl)-6-(phenylthiomethyl)-[1,2,4]-
triazolo[3,4-b][1,3,4]thiadiazole (25). From sodium phenylthiolate (33
mg). Yield: 73 mg (72%); oil. 1H NMR (CDCl3): δ 7.37 (m, 5H, ArH); 4.77
(d, 1H, J 1 ,2 = 5.6 Hz, H-1ꢁ); 4.71 (d, 1H, J 2 ,3 = 5.6 Hz, H-2ꢁ); 4.56 (t, 1H,
ꢁ
ꢁ
ꢁ
ꢁ
J 3 ,4 b = 2.3 Hz, H-3ꢁ); 4.27 (s, 2H, CH2S); 3.92 (dd, 1H, J 3 ,4 a = 2.3 Hz,
ꢁ
ꢁ
ꢁ
ꢁ
H-4ꢁa); 3.73 (dd, 1H, J 4 a,4 b = 12.2 Hz, H-4ꢁb); 1.40, 1.31 (2 × s, 6H,
CMe2). 13C NMR (CDCl3): δ 174.7 (C-6); 167.0 (C-3); 141.8 (C-8); 135.0,
130.7, 131.4, 129.0, 127.1 (Ar-C); 113.1 (CMe2); 82.6 (C-2ꢁ); 78.2 (C-1ꢁ);
75.6 (C-3ꢁ); 62.0 (C-4ꢁ); 40.6 (CH2S); 26.6, 25.5 (CMe2). MS: m/z (FAB) 431
(M+Na)+.
ꢁ
ꢁ
6-(Benzylthiomethyl)-3-(1,2-O-isopropylidene-D-ribo-tetritol-1-yl)-[1,2,4
]triazolo[3,4-b][1,3,4]thiadiazole (26). From benzyl mercaptan (31 mg)
and Et3N (25 mg, 0.25 mmol). Yield: 88 mg (86%); m.p. 82–85◦C. 1H NMR
(CDCl3): δ 7.32–7.24 (m, 5H, ArH); 4.83 (d, 1H, J 1 ,2 = 5.6 Hz, H-1ꢁ);
ꢁ
ꢁ
4.78 (d, 1H, J 2 ,3 = 5.6 Hz, H-2ꢁ); 4.62 (t, 1H, J 3 ,4 b = 2.0 Hz, H-3ꢁ); 3.99
ꢁ
ꢁ
ꢁ
ꢁ
(dd, 1H, J 3 ,4 a = 2.3 Hz, H-4ꢁa); 3.80 (dd, 1H, J 4 a,4 b = 12.0 Hz, H-4ꢁb);
3.09 (br s., 4H, CH2SCH2Ph); 1.46, 1.37 (2 × s, 6H, CMe2). 13C NMR
(DMSO-d6): δ 175.0 (C-6); 160.1 (C-3); 151.6 (C-8); 129.4, 128.7, 128.4,
127.4 (Ar-C); 113.0 (CMe2); 83.7 (C-2ꢁ); 78.3 (C-1ꢁ); 75.5 (C-3ꢁ); 61.7 (C-4ꢁ);
45.7 (CH2SCH2Ph); 41.5 (CH2SCH2Ph); 26.7, 25.4 (CMe2). Anal. calc. for
ꢁ
ꢁ
ꢁ
ꢁ

Microwave-Assisted Synthesis of Novel Acyclic C-Nucleosides
481
C18H22N4O4S2 (422.52): C, 51.17; H, 5.25; N, 13.26. Found; C, 50.95; H,
5.19; N, 13.03. MS: m/z (FAB) 423 (M+H)+.
3-(1,2-O-Isopropylidene-D-ribo-tetritol-1-yl)-6-((4-methoxyphenylthio)methyl)-
[1,2,4] triazolo[3,4-b][1,3,4]thiadiazole (27). From 4-methoxybenzenethiol
(35 mg) and Et3N (25 mg, 0.25 mmol). Yield: 93 mg (90%); m.p. 76–78◦C.
1H NMR (CDCl3): δ 7.36 (d, 2H, J = 9.0 Hz, Ar-H); 6.82 (d, 2H, J = 9.0
Hz, ArH); 4.81 (br s, 2H, H-1ꢁ, H-2ꢁ); 4.57 (t, 1H, J 3 ,4 b = 2.3 Hz, H-3ꢁ); 4.11
ꢁ
ꢁ
(s, 2H, CH2S); 3.85 (dd, 1H, J 3 ,4 a = 2.3 Hz, H-4ꢁa); 3.78 (dd, 1H, J 4a ,4 b
= 12.0 Hz H-4ꢁb); 3.77 (s, 3H, OMe); 1.43, 1.31 (2 × s, 6H, CMe2). 13C
NMR (CDCl3): δ 175.1 (C-6); 160.1 (C-3); 157.9 (C-8); 133.7, 128.6, 127.4,
125.0 (Ar-C); 114.4 (CMe2); 82.7 (C-2ꢁ); 78.3 (C-1ꢁ); 75.6 (C-3ꢁ); 61.4 (C-4ꢁ);
55.2 (OMe); 45.7 (CH2S); 26.6, 25.3 (CMe2). Anal. calc. for C18H22N4O5S2
(438.52): C, 49.30; H, 5.06; N, 12.78. Found; C, 49.02; H, 4.89; N, 12.52.
MS: m/z (FAB) 439 (M+H)+.
ꢁ
ꢁ
ꢁ
ꢁ
6-(Alkyl/aryl-thiomethyl)-3-(D-ribo-tetritol-1-yl)[1,2,4]triazolo[3,4-
b][1,3,4]thiadiazoles (28–30)
These compounds were prepared from 25–276 (0.30 mmol), as oily or
solid product, by following the procedure used for the preparation of 4.
3-(D-Ribo-tetritol-1-yl)-6-(phenylthio)methyl)-[1,2,4]triazolo[3,4-b][1,3,4
1
]thiadiazole (28). From 25 (122 mg). Yield: 94 mg (85%); oil. H NMR
(DMSO-d6): δ 7.41–7.23 (m, 5H, ArH); 4.41 (d, 1H, J 1 ,2 = 5.4 Hz, H-1ꢁ);
ꢁ
ꢁ
4.22 (dd, 1H, J 2 ,3 = 5.4 Hz, H-2ꢁ); 4.19 (t, 1H, J 3 ,4 b = 2.3 Hz, H-3ꢁ); 4.12
(br s., 6H, CH2S, 4xOH); 3.56 (m, 2H, H-4ꢁa, H-4ꢁb). 13C NMR (DMSO-d6):
δ 176.4 (C-6); 166.2 (C-3); 148.0 (C-8); 134.6, 129.1, 128.9, 1267.4 (Ar-C);
85.3 (C-2ꢁ); 69.3 (C-3ꢁ); 68.6 (C-1ꢁ); 60.4 (C-4ꢁ); 37.0 (CH2S). MS: m/z (FAB)
391 (M+Na)+.
ꢁ
ꢁ
ꢁ
ꢁ
6-(Benzylthiomethyl)-3-(D-ribo-tetritol-1-yl)[1,2,4]triazolo[3,4-b][1,3,4
]thiadiazole (29). From 26 (127 mg). Yield: 95 mg (83%); oil. 1H
ꢁ
ꢁ
NMR (DMSO-d6): δ 7.42–7.28 (m, 5H, ArH); 4.46 (d, 1H, J 1 ,2 = 5.6 Hz,
H-1ꢁ); 4.18 (d, 1H, J 2 ,3 = 5.4 Hz, H-2ꢁ); 4.01 (t, 1H, J 3 ,4 b = 2.5 Hz, H-3ꢁ);
4.82–4.20 (br s, 4H, 4xOH); 4.07 (s, 2H, SCH2); 3.55 (m, 2H, H-4ꢁa, H-4ꢁb).
13C NMR (DMSO-d6): δ 176.4 (C-6); 166.2 (C-3); 148.0 (C-8); 134.6, 129.1,
128.9, 1267.4 (Ar-C); 85.3 (C-2ꢁ); 69.3 (C-3ꢁ); 68.6 (C-1ꢁ); 60.4 (C-4ꢁ); 37.9
(CH2S). MS: m/z (FAB) 405 (M+Na)+.
ꢁ
ꢁ
ꢁ
ꢁ
3-(D-Ribo-tetritol-1-yl)-6-((4-methoxyphenylthio)methyl)-[1,2,4]triazolo[3,4-
b][1,3,4] thiadiazole (30). From 27 (132 mg). Yield: 108 mg (90%); oil.1H
NMR (DMSO-d6): δ 7.35 (d, 2H, J = 8.9 Hz, Ar-H); 6.91 (d, 2H, J = 8.9 Hz,
Ar-H) 4.41 (d, 1H, J 1 ,2 = 5.4 Hz, H-1ꢁ); 4.22 (d, 1H, J 2 ,3 = 5.4 Hz, H-2ꢁ);
ꢁ
ꢁ
ꢁ
ꢁ
4.12 (t, 1H, J 3 ,4 b = 2.0 Hz, H-3ꢁ); 4.06 (br s, 6H, CH2S, 4xOH); 3.59 (s,
3H, OMe); 3.56 (m, 2H, H-4ꢁa, H-4ꢁb). 13C NMR (DMSO-d6): δ 176.6 (C-6);
166.1 (C-3); 148.7 (C-8); 133.3, 124.6, 121.6, 114.7 (Ar-C); 85.4 (C-2ꢁ); 69.4
(C-3ꢁ); 68.7 (C-1ꢁ); 60.5 (C-4ꢁ); 55.2 (OMe); 41.2. (CH2S). MS: m/z (FAB)
421 (M+Na)+.
ꢁ
ꢁ

482
Y. A. Al-Soud et al.
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