Synthesis of N-substituted 1-amino-2,3-dihydro-1H-imidazole-2-thione-N-nucleosides and S-glycosylated derivatives

Article abstract of DOI:10.1081/NCN-120021429

Fusion of the N-substituted 1-amino-2,3-dihydro-1H-imidazole-2-thiones 1-4 with the peracylated ribose 5 in the presence of iodine afforded the N-nucleosides 6-9 in moderate yields. Deblocking with NaOMe/MeOH gave the free nucleosides 10-13. Alternatively, silylation of 4 followed by ribosylation with 5 in the presence of TMSOTf as catalyst afforded 9 in moderate yield. Ribosylation of 4 with the chlorodeoxyribose derivative 15 as well as 5 in the presence of NaH in DMF afforded the thioglycosides 16 and 18, respectively. Deblocking of 16 and 18 with NaOMe/MeOH gave the free S-thioglycosides 17 and 19, respectively. Thermal rearrangement of 19 at high temperature in the presence of iodine furnished 13 in low yield. The new free nucleosides and thioglycosides were inactive against HIV-1 and HIV-2 induced cytopathicity in human MT-4 lymphocyte cells.

Full text of DOI:10.1081/NCN-120021429

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Synthesis of N-Substituted 1-Amino-2,3-dihydro-1H-
imidazole-2-thione-N-nucleosides and S-Glycosylated
Derivatives
Iman A. Al-Masoudi a , Ahmed I. Khodair b , Yaseen A. Al-Soud c & Najim A. Al-Masoudi d e
a College of Veterinary , University of Basrah , Basrah, Iraq
b Chemistry Department , Faculty of Education , Tanta University (Kafr El-Sheikh Branch) ,
Kafr El-Sheikh, Egypt
c College of Science , Department of Chemistry , University of Al al-Bayt , Al-Mafraq, Jordan
d Fakultät für Chemie , Universität Konstanz , Konstanz, Germany
e Fakultät für Chemie , Universität Konstanz , Postfach 5560, D-78457, Konstanz, Germany
Published online: 07 Feb 2007.
To cite this article: Iman A. Al-Masoudi , Ahmed I. Khodair , Yaseen A. Al-Soud & Najim A. Al-Masoudi (2003) Synthesis
of N-Substituted 1-Amino-2,3-dihydro-1H-imidazole-2-thione-N-nucleosides and S-Glycosylated Derivatives, Nucleosides,
Nucleotides and Nucleic Acids, 22:3, 299-307, DOI: 10.1081/NCN-120021429
To link to this article: http://dx.doi.org/10.1081/NCN-120021429
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS
Vol. 22, No. 3, pp. 299–307, 2003
Synthesis of N-Substituted 1-Amino-2,3-dihydro-
1H-imidazole-2-thione-N-nucleosides and
S-Glycosylated Derivatives
Iman A. Al-Masoudi,1 Ahmed I. Khodair,2 Yaseen A. Al-Soud,3
and Najim A. Al-Masoudi4,
*
1College of Veterinary, University of Basrah, Basrah, Iraq
2Chemistry Department, Faculty of Education, Tanta University
(Kafr El-Sheikh Branch), Kafr El-Sheikh, Egypt
3College of Science, Department of Chemistry, University of
Al al-Bayt, Al-Mafraq, Jordan
4Fakulta¨t fur Chemie, Universita¨t Konstanz, Konstanz, Germany
¨
ABSTRACT
Fusion of the N-substituted 1-amino-2,3-dihydro-1H-imidazole-2-thiones 1-4
with the peracylated ribose 5 in the presence of iodine afforded the N-nucleosides
6-9 in moderate yields. Deblocking with NaOMe=MeOH gave the free nucleo-
sides 10-13. Alternatively, silylation of 4 followed by ribosylation with 5 in the
presence of TMSOTf as catalyst afforded 9 in moderate yield. Ribosylation of
4 with the chlorodeoxyribose derivative 15 as well as 5 in the presence of NaH
in DMF afforded the thioglycosides 16 and 18, respectively. Deblocking of 16
and 18 with NaOMe=MeOH gave the free S-thioglycosides 17 and 19, respec-
tively. Thermal rearrangement of 19 at high temperature in the presence of iodine
furnished 13 in low yield. The new free nucleosides and thioglycosides were
*Correspondence: Najim A. Al-Masoudi, Fakulta¨t fur Chemie, Universita¨t Konstanz,
¨
Postfach 5560, D-78457 Konstanz, Germany; Fax: þ49 7531 34435; E-mail: NajimAl-Masoudi@
uni-konstanz.de.
299
DOI: 10.1081/NCN-120021429
Copyright # 2003 by Marcel Dekker, Inc.
1525-7770 (Print); 1532-2335 (Online)
www.dekker.com

300
Al-Masoudi et al.
inactive against HIV-1 and HIV-2 induced cytopathicity in human MT-4 lympho-
cyte cells.
Key Words: Antiviral activity; Imidazole-2-thiones; N-Nucleosides; S-Glyco-
sides; Ribosylation.
Various heterocycles bearing the thioureylene group are known to possess inter-
esting biological properties.[1] For example, methimazole (1-methylimidazole-
2-thione, TapazoleÕ) is currently used for the treatment of thyroid gland disorder.[2]
Other derivatives are used for the treatment of arthritis[3,4], cardiovascular dis-
eases[5,6], antiinflimmatory activity[7] as well as anti-HIV agents.[8] It is well known
that various nucleoside analogues played an important role in the field of cancer
chemotherapy and viral diseases.[9] Imbach et al.[10] have reported the first imidazole
nucleosides possessing the thioureuylene group and evaluated their chemotherapeutic
properties in comparison to the methimazole. These prompted us to synthesize new
2-mercapto imidazole nucleosides by ribosylation of some selected imidazole bases
namely, the N-substituted 1-amino-2,3-dihydro-1H-imidazole-2-thiones.[11]
RESULTS AND DISCUSSION
The site of ribosylation of the imidazole bases[11] 1-4 were first examined by the
fusion procedure, following Imbach et al. method.[10] Thus, 1-4 (1.1 equivalents) fused
with 1-O-acetyl-2,3,5-tri-O-benzoyl-b-D-ribofuranose (5) in the presence of iodine
afforded, after chromatographic purification, the N-nucleosides 6-9 in 41, 45, 40
and 55% yields, respectively, with some other products which are presumably the
S-ribosides, N,S-ribosides or decomposed products. 1-(4-Chlorophenylamino)-2,3-
dihydro-4-methyl-5-phenyl-1H-imidazole-2-thione (4) has been selected for the
Hilbert-Johnson-Birkofer procedure[12] to improve the selective N-ribosylation. Thus,
silylation of 4 with hexamethyldisilazane (HMDS) gave the silylated product 14,
which was treated with the sugar derivative 5 in dry MeCN as solvent, and
trimethylsilyl trifluoromethanesulfonate (TMSOTf)[13] as catalyst at 75ꢀC for 3 h to
give, after column chromatography, 9 in 53% yield. Deblocking of 6-9 with
NaOMe=MeOH at room temperature for 16 h afforded the free nucleosides 10-13 in
73, 70, 68 and 78% yields, respectively (Sch. 1). The structures of 6-13 were character-
ized from their 1H NMR and mass spectra. The anomeric coupling constants of 6-13
are typical for b-configurated ribofuranoses (between 5.1 and 5.5 Hz). The rotating
frame nuclear overhauser effect (ROE)[14] between H-10 and H-40 is an additional
proof for b-configuration. The proton spin systems were identified from DQF-
COSY[15] and ROESY spectra, since showed a good evidance for ribosylation of 1-
4 via the N-site of the imidazole molecule. This was confirmed by the 3JC,H correlation
of C-2 at dC 162.2 and H-10 at dH 6.45 of 9. The nucleoside 9 was selected for further
NMR study. The signal at dC 120.9, assigned to C-4, has a cross peak to dH 6.45 of H-10
in the HMQC[16] spectrum. Moreover, C-2 resonated at highest field (dC 162.2) due to
the shielding nature around (C¼S) bond, and these data showed an additional proof
for the N-glycosylation and excluded the substitution at the sulfur atom. The above

1H-Imidazole-2-thione-N-nucleosides and S-Glycosylated Derivatives
301
Scheme 1.
argument is in agreement with the spectral data obtained by Shantle et al.[11] during
the N3-methylation of N1-substituted-4-methyl-5-phenyl-1H-imidazole-2-thione.
Further study was made with the 2-deoxyribose. When compound 4 was reacted
with 1.1 equivalent of NaH in anhyd. DMF followed by 1.1 equivalent of chloro-
deoxysugar 15 at 60ꢀC for 2 h gave, after chromatographic separation, the thio-
glycoside 16 in 35% yield. The structure of 16 was confirmed by the COSY,
ROESY, HMQC and HMBC NMR experiments as well as the mass spectrum. The
1H-NMR spectrum of 16 showed the anomeric ratio (a:b) to be about 1 : 3, since
H-10 (b-anomer, from HMBC experiment) appeared as a doublet of doublets at dH

302
Al-Masoudi et al.
0
0
0
0
7.07 (J1 ,2 a ¼ 5.5 Hz; J1 ,2 b ¼ 3.5 Hz). The b-configuration of 16 was further
confirmed by NOE experiment.[16] Thus, irradiation of the H-10 signal led to
enhancement of the signal for H-40 (2.8%). C-2 resonated at lower field dC 142.1,
indicating the S-glycosylation and excluded the N-substitution, and these data again
is in agreement with those of the S-methyl-imidazole derivative obtained by Schantle
et al.[11] Similarly, treatment of 4 with the sugar derivative 5 in DMF and NaH gave,
after chromatography, the thioglycoside 18 in 38% yield. Removal of the benzoyl
groups of 18 with NaOMe=MeOH afforded the free thioglycoside 19 in 78% yield.
The anomeric coupling constants of 18 and 19 (5.3, 4.9 Hz, respectively) are indi-
cated for the b-configuration. The signals at dC 142.5 and 146.3, which attributed
to C-2 of 18 and 19, respectively, are characteristic for the site of ribosylation at
the sulfur atom rather than nitrogen. Proton bearing carbon of 18 was detected
1
1
by H-1H and H-13C COSY spectra as well as the HMQC spectra.[16] The assign-
ment of the S-glycosylation was further studied by gradient selected HMBC[17] via
the 3JC,H coupling between H-10 (dH 6.10) and C-2 (dC 142.5), along with disappear-
ance of such coupling between H-10 and C-4. The residual sugar protons of both 18
and 19 were fully analysed (see experimental part).
When the S-glycoside 19 was subjected to the high temperature (170–180ꢀC) by
applying Halasa et al. method[18] in the presence of iodine as catalyst, it was
rearranged into the N-nucleoside 13 (18% yield). The low yield of 13 is presumably
due to the thermal decomposition of 19 into an unidentified products, separated by
the chromatography.
The imidazole N-nucleosides and S-thioglycosides 9-13, 16 and 19 were evalu-
ated in vitro for their inhibitory activity of HIV-1 (III B) and HIV-2 (ROD) in
human MT-4 lymphocyte cells. All compounds were inactive against both HIV-1
and HIV-2 up to 100 mg=mL. Furthermore, compounds 9-13 are under investigation
for the treatment of thyroid gland disorder.
Experimental
1
General procedure. Melting points are uncorrected. H- and 13C-NMR spectra
were recorded on AC 250 and 600 MHz spectrometers, using tetramethylsilane
(TMS) as internal standard, with d: chemical shift in ppm, and coupling constants
in Hz. Mass spectra were measured in glycerol as matrix, meanwhile, some molecular
ions were measured with sodium ions.
Preparation of N-substituted 1-amino-4-methyl-5-phenyl-1H-imidazole-2-thione-
N-nucleosides. General procedure. The desired bases 1-4 (2.21 mmol), the sugar
derivative 5 (1.22 g, 2.43 mmol, 1.1 equiv.) and iodine (5.2% mole per mole of an
imidazole base) was fused at 160ꢀC for 20 min. under vacuum. After cooling,
the brown residue was dissolved in CHCl3 (10 mL), filtered and poured onto SiO2 col-
umn (50 g). Elution first with CHCl3, then with CHCl3-MeOH (49 : 1) afforded two
compounds. The first eluted compounds was were unidentified products. The second
eluted compounds were characterized as the N-nucleosides 6-9, mostly as foam.
3-(2,3,5-Tri-O-benzoyl-b-D-ribofuranosyl)-4-methyl-5-phenyl-1-phenylamino-1H-
imidazole-2-thione (6). From 1 (0.62 g). Yield: 0.66 g, (41%); foam. dH (CDCl3):

1H-Imidazole-2-thione-N-nucleosides and S-Glycosylated Derivatives
303
8.89 (s, 1H, NH); 7.40–7.27 (m, 5H, C5-Ph); 7.11 (dd, 1H, J ¼ 8.1 Hz, NH-Ph); 6.72
0
0
0
(t, 2H, J ¼ 7.5 Hz, NH-Ph); 6.51 (d, 1H, J1 ,2 ¼ 5.4 Hz, H-1 ); 6.48 (d, 2H, J ¼ 8.2 Hz,
0
0
0
0
0
00
0
NH-Ph); 5.90 (t, 1H J2 ,3 ¼ 5.5 Hz, H-2 ); 5.85 (t, 1H, J3 ,4 ¼ 4.2 Hz, H-3 ); 4.97 (dd,
0
00
0
0
1H, J4 ,5 ¼ 3.5 Hz, H-4 ); 4.95 (dd, 1H, J4 ,5 ¼ 3.0 Hz, H-5 ); 4.85 (dd, 1H,
00
0
00
J5 ,5 ¼ 12.5 Hz, H-5 ); 2.17 (s, 3H, Me). Anal. calc. for C42H35SN3O7 (725.8): C,
69.50; H, 4.86; N, 5.79. Found: C, 69.46; H, 4.76; N, 5.57. MS: m=z (FAB) 726
(MH)þ.
3-(2,3,5-Tri-O-benzoyl-b-D-ribofuranosyl)-1-(4-methoxyphenylamino)-4-methyl-
5-phenyl-1H-imidazole-2-thione (7). From 2 (0.67 g). Yield: 0.75 g; (45%); m.p. 80–
86ꢀC. dH (CDCl3): 9.20 (s, 1H, NH); 7.38–7.31 (m, 5H, C5-Ph); 7.17, 7.15 (2d,
0
0
0
2H, J ¼ 8.9 Hz, NH-4-OMePh); 6.62 (d, 1H, J1 ,2 ¼ 5.5 Hz, H-1 ); 6.48 (2d, 2H,
J ¼ 8.9 Hz, NH-4-OMePh); 5.88 (m, 2H, H-20, H-30); 4.99 (t, 1H, J4 ,5 ¼ 2.9 Hz,
H-40); 4.96–4.90 (m, 2H, H-50, H-500); 2.15 (s, 3H, Me). Anal. calc. for C43H38SN3O8
(756.9): C, 68.24; H, 5.06; N, 5.55. Found: C, 68.02; H, 4.98; N, 5.24. MS: m=z
(FAB) 780 (MNa)þ.
0
00
3-(2,3,5-Tri-O-benzoyl-b-D-ribofuranosyl)-4-methyl-1-(4-nitrophenylamino)-5-
phenyl-1H-imidazole-2-thione (8). From 3 (0.72 g). Yield: 0.68 g, (40%); m.p. 110–
115ꢀC. dH (CDCl3): 10.32 (s, 1H, NH); 7.28–7.21 (m, 5H, C5-Ph); 8.11, 8.14
(2d, 2H, J ¼ 9.5 Hz, NH-4-NO2Ph); 6.59 (2d, 2H, J ¼ 9.5 Hz, NH-4-NO2Ph); 6.47
0
0
0
0
0
(d, 1H, J1 ,2 ¼ 5.3 Hz, H-1 ); 5.82–5.77 (m, 2H, H-2 , H-3 ); 4.94 (t, 1H,
0
0
0
00
0
0
0
00
J4 ,5 ¼ 3.5 Hz, H-4 ); 4.99 (dd, 1H J4 ,5 ¼ 3.0 Hz, H-5 ); 4.96 (dd, 1H, J5 ,5 ¼ 12.3 Hz,
Hz, H-500); 2.17 (s, 3H, Me). Anal. calc. for C42H34SN4O9 (770.8): C, 65.45; H, 4.45;
N, 7.27. Found: C, 65.33; H, 4.36; N, 7.05. MS: m=z (FAB) 793 (MNa)þ.
3-(2,3,5-Tri-O-benzoyl-b-D-ribofuranosyl)-1-(4-chlorophenylamino)-4-methyl-5-
phenyl-1H-imidazole-2-thione (9). Method a. From 4 (0.70 g). Yield: 0.93 g, (55%);
m.p. 85–91ꢀC. dH (600 MHz, COSY, ROESY, HMQC, HMBC, CDCl3): 9.17
(s, 1H, NH); 7.37–7.33 (m, 5H, C5-Ph); 6.98, 6.90 (2d, 2H, J ¼ 8.0 Hz, NH-4-ClPh);
0
0
0
6.45 (d, 1H, J1 ,2 ¼ 5.2 Hz, H-1 ); 6.39, 6.30 (2d, 2H, J ¼ 8.0 Hz, NH-4-ClPh); 5.85–
5.80 (m, 2H, H-20, H-30); 4.96 (t, 1H, J4 ,5 ¼ 3.3 Hz, H-4 ); 4.92 (dd, 1H
0
0
00
0
00
0
0
0
00
J4 ,5 ¼ 2.8 Hz, H-5 ); 4.87 (dd, 1H, J5 ,5 ¼ 12.5, H-5 ); 2.14 (s, 3H, Me). dC(CDCl3):
66.1; 165.1, 164.6 (C¼O); 162.2 (C-2); 133.4–129.0 (Ar); 126.8 (C-5); 120.9 (C-4);
114.3, 112.5 (Ph); 90.6 (C-10); 82.0 (C-40); 74.6 (C-30); 70.0 (C-30); 62.8 (C-50); 10.8
(C4-Me). Anal. calc. for C42H34ClSN3O7 (760.3): C, 66.35; H, 4.51; N, 5.53. Found:
C, 66.25; H, 4.21; N, 5.39. MS: m=z (FAB) 760=762 (MH)þ.
Method b. To a suspended 4 (0.80 g, 2.50 mmol) in anhyd. MeCN (25 mL) was
added hexamethyldisilazane (20 mL) and the reaction mixture was heated under
reflux for 16 h. After cooling, the solution was evaporated to drynress under anhyd.
condition, then dissolved in MeCN (25 mL). To this, a solution of 5 (1.38 g,
2.7 mmol) in MeCN (20 mL) was added, followed by the addition of TMSOTf
(1.1 mmol), dropwise and the mixture was heated at 75ꢀC for 3 h. After cooling, a
saturated aqueous solution of NaHCO3 was added and the resulting mixture
extracted with CH2Cl2 (3 ꢁ 30 mL). The combined organic fractions were washed
with saturated NaCl solution, dried (Na2SO4), filtered and evaporated to dryness.
The amorphous obtained was purified by flash chromatography, using MeOH, in

304
Al-Masoudi et al.
gradient, (0–2%) and CHCl3 as eluent to give 9 (1.37 g, 72%) as amorphous
compound. All the physical properties are similar to those of the authentic sample
prepared in method a.
Preparation of free N-Nucleosides 10-13 derived from compounds (6-9). General
procedure. A solution of the acylated nucleoside (0.80 mmol) in 0.20 M NaOMe=
MeOH solution (20 mL) was stirred at room temperature for 18 h. The solution
was evaporated to dryness and the residue was partitioned between water (35 mL)
and ether (3 ꢁ 30 mL). The aqueous layer was evaporated to dryness and the residue
was co-evaporated with EtOH (3 ꢁ 30 mL) to give a crude product. Recrystallization
from EtOH afforded the desired free N-nucleosides.
4-Methyl-5-phenyl-1-phenylamino-3-(b-D-ribofuranosyl)-1H-imidazole-2-thione
(10). From 6 (0.58 g). Yield: 0.24 g, (73%); m.p. 200–205ꢀC. dH (DMSO-d6): 9.00
(s, 1H, NH); 7.42–7.34 (m, 5H, C5-Ph); 7.15 (dd, 1H, J ¼ 8.0 Hz, NH-Ph); 6.81 (t,
0
0
2H, J ¼ 7.2 Hz, NH-Ph); 6.58 (d, 2H, J ¼ 8.0 Hz, NH-Ph); 6.51 (d, 1H, J1 ,2 ¼ 5.4 Hz,
0
0
0
H-1 ); 5.83 (t, 1H, J ¼ 5.9 Hz, C5 -OH); 5.33 (d, 1H, J ¼ 5.7 Hz, C2 -OH); 5.11 (d, 1H,
0
0
0
0
0
J ¼ 3.5 Hz, C3 -OH); 4.18 (dd, 1H, J2 ,3 ¼ 5.3 Hz, H-2 ); 4.11-3.48 (m, 4H, H-3 -H-
500); 2.23 (s, 3H, Me). Anal calc. for C21H23SN3O4 (413.5): C, 61.00; H, 5.61; N,
10.16. Found: C, 60.82; H, 5.53; N, 9.89. MS: m=z (FAB) 436 (MNa)þ.
1-(4-Methoxyphenylamino)-4-methyl-5-phenyl-3-(b-D-ribofuranosyl)-1H-imida-
zole-2-thione (11). From 7 (0.61 g). Yield: 0.25 g, (70%); m.p. 205–209ꢀC. dH
(DMSO-d6): 9.31 (s, 1H, NH); 7.48–7.37 (m, 5H, C5-Ph); 7.20, 7.16 (2d, 2H,
0
0
0
J ¼ 9.0 Hz, 4-OMePh); 6.63 (d, 1H, J1 ,2 ¼ 5.3 Hz, H-1 ); 6.54 (2d, 2H, J ¼ 9.0 Hz,
0
0
NH-4-OMePh); 5.84 (t, 1H J ¼ 5.7 Hz, C5 -OH); 5.35 (d, 1H, J ¼ 5.5 Hz, C2 -OH);
0
0
0
0
5.13 (d, 1H, J ¼ 3.7 Hz, C3 -OH); 4.21 (dd, 1H, J2 ,3 ¼ 5.2 Hz, H-2 ); 4.14-3.51 (m,
4H, H-30-H-500); 2.24 (s, 3H, Me). Anal calc. for C22H25SN3O5 (443.5): C, 59.58;
H, 5.68; N, 9.47. Found: C, 59.27; H, 5.59; N, 9.28. MS: m=z (FAB) 466 (MNa)þ.
4-Methyl-1-(4-nitrophenylamino)-5-phenyl-3-(b-D-ribofuranosyl)-1H-imidazole-
2-thione (12). From 8 (0.62 g). Yield: 0.25 g, (68%); m.p. 239–242ꢀC. dH (DMSO-
d6): 10.35 (s, 1H, NH); 7.34–7.29 (m, 5H, C5-Ph); 8.15, 8.19 (2d, 2H, J ¼ 9.5 Hz,
0
0
0
4-NO2Ph); 6.63 (2d, 2H, J ¼ 9.5 Hz, 4-NO2Ph); 6.52 (d, 1H, J1 ,2 ¼ 5.2 Hz, H-1 );
0
0
5.75 (t, 1H J ¼ 5.7 Hz, C5 -OH); 5.30 (d, 1H, J ¼ 5.6 Hz, C2 -OH); 4.98 (d, 1H,
0
0
0
0
0
J ¼ 3.5 Hz, C3 -OH); 4.15 (dd, 1H, J2 ,3 ¼ 5.2 Hz, H-2 ); 3.98-3.31 (m, 4H, H-3 -H-
500); 2.20 (s, 3H, Me). Anal calc. for C21H22SN4O6 (455.5): C, 55.01; H, 4.84; N,
12.22. Found: C, 54.85; H, 4.74; N, 11.82. MS: m=z (FAB) 477=479 (MNa)þ.
1-(4-Chlorophenylamino)-4-methyl-5-phenyl-3-(b-D-ribofuranosyl)-1H-imidazole-
2-thione (13). Method a. From 9 (0.61 g). Yield: 0.28 g, (78%); m.p. 189–193ꢀC. dH
(DMSO-d6): 9.19 (s, 1H, NH); 7.39–7.37 (m, 5H, C5-Ph); 7.01, 6.95 (2d, 2H,
0
0
0
J ¼ 8.0 Hz, 4-ClPh); 6.53 (2d, 1H, J1 ,2 ¼ 5.0 Hz, H-1 ); 6.42, 6.35 (2d, 2H, J ¼ 8.0 Hz,
0
4-ClPh); 2.17 (s, 3H, Me). 5.82 (t, 1H J ¼ 5.9 Hz, C5 -OH); 5.30 (d, 1H, J ¼ 5.8 Hz,
0
0
0
0
0
C2 -OH); 5.13 (d, 1H, J ¼ 3.6 Hz, C3 -OH); 4.13 (dd, 1H, J2 ,3 ¼ 5.1 Hz, H-2 );
4.09-3.38 (m, 4H, H-30-H-500); 2.23 (s, 3H, Me). Anal. calc. for C21H22ClSN3O4

1H-Imidazole-2-thione-N-nucleosides and S-Glycosylated Derivatives
305
(447.9): C, 55.93; H, 5.59; N, 9.32. Found: C, 55.74; H, 5.49; N, 9.16. MS: m=z
(FAB) 451=453 (MH)þ.
Method b. A mixture of 19 (200 mg, 0.44 mmol) and iodine (20 mg) was heated at
170–180ꢀC for 7 h. After cooling, the brown solid was partitioned between water
(10 mL) and ether (3 ꢁ 10 mL) and the aqueous extract was evaporated to dryness.
The residue was co-evaporated with EtOH (4 ꢁ 10 mL) and chromatographed on
short column of silica gel (CHCl3-MeOH 9 : 1, as eluent) to give 13 (35 mg, 18%),
m.p., mixed m.p. and all the physical data were identical to those of the authentic
sample prepared in method a.
2-(3,5-Di-O-4-chlorobenzoyl-2-deoxy-b-D-erythropentofuranosylsulfanyl)-1-(4-
chlorophenylamino)-4-methyl-5-phenyl-1H-imidazole (16). To a solution of 4 (0.50 g,
1.58 mmol) in DMF (10 mL) was added NaH (0.11 g, 4.76 mmol) under argon and
the suspension was stirred at 60ꢀC. After 2 h, the chloro sugar 15 (0.58 g, 1.45 mmol)
was added and the solution was stirred at room temperature for 18 h. The solvent
was evaporated and the residue was partitioned between CHCl3 (3 ꢁ 30 mL) and
water (30 mL). The combined organic extracts were dried (Na2SO4), filtered and
evaporated to dryness. The crude residue was dissolved in CHCl3 (5 mL) and poured
onto SiO2 column (50 g). Elution, in gradient, with MeOH (0–2%) and CHCl3
afforded 16 (0.28 g, 25%) as amorphous, m.p. 75–81ꢀC. dH (600 MHz, COSY,
ROESY, HMQC, HMBC, CDCl3): 9.17 (s, 1H, NH); 8.00-7.96 (m, 4H, Ar); 7.45–
6.89 (m, 8H, Ar); 7.07 (dd, 1H, J1 ,2 a ¼ 3.5 Hz, J1 ,2 b ¼ 5.5 Hz, H-10); 6.62, 6.53
0
0
0
0
0
0
0
0
(2d, 4H, J ¼ 8.2 Hz, 4-ClPh); 5.67 (dt, J3 ,4 ¼ 7.6 Hz, H-3 ); 4.46 (m, 1H, H-4 );
4.80 (m, 1H, H-500); 4.58 (m 1H, H-50); 2.90 (ddd, 1H, H-20a); 2.70 (dt, 1H, H-
20b); 2.35 (s, 3H, Me). dC(CDCl3): 165.0, 165,2 (C ¼ O); 142.1 (C-2); 133.2–129.0
(Ar); 126.3 (C-5); 120.0 (C-4); 114.4, 112.5 (Ph); 86.2 (C-10); 81.0 (C-40); 73.8 (C-
30); 64.0 (C-50); 35.9 (C-20); 10.9 (C4-Me). Anal. calc. for C35H28Cl3SN3O5 (709.1):
C, 59.29; H, 3.98; N, 5.93. Found: C, 59.01; H, 5.81.; N, 5.72. MS: m=z (FAB)
708=710 (MH)þ.
1-(4-Chlorophenylamino)-2-(2-deoxy-b-D-erythropentofuranosylsulfanyl)-4-methyl-
5-phenyl-1H-imidazole (17). A suspension of 16 (0.40 g, 0.56 mmol) in 0.2 M
NaOMe=MeOH (10 mL) was stirred at room temperature for 18 h. The solution was
evaporated to dryness and the residue was partitioned between ether (3 ꢁ 30 mL) and
water (20 mL). The aqueous layer was evaporated to dryness and the residued was
co-evaporated with EtOH (3 ꢁ 20 mL). The residue was dissolved in MeOH (2 mL)
and co-evaporated with SiO2 (2 g), and then poured on SiO2 column (10 g). Elution,
in gradient, with MeOH (0–10%) and CHCl3 gave 17 (0.21 g, 85%); m.p. 179–183ꢀC
(from EtOH). dC (DMSO-d6): 9.21 (s, 1H, NH); 7.39–7.31 (m, 5H, Ph); 6.73, 6.59
(2d, 4H, J ¼ 8.1 Hz; 4-ClPh); 6.61 (dd, 1H, J1 ,2 a ¼ 4.2 Hz, J1 ,2 b ¼ 5.5 Hz, H-10);
0
0
0
0
0
0
5.15 (d, 1H, J ¼ 1.5 Hz, C3 -OH); 5.00 (t, 1H, J ¼ 3.5 Hz, C5 -OH); 4.55 (m, 1H,
H-400); 4.30 (m, 1H, H-30); 2.48–3.52 (m, 2H, H-50, H-500); 2.84 (m, 1H, H-20); 2.10
(m, 1H, H-200); 2.37 (s, 3H, C4-Me). dC (DMSO-d6): 142.0 (C-2); 134.1-130.2 (Ar);
126.5 (C-5); 120.1 (C-4); 114.9, 112.5 (Ph); 87.3 (C-10); 90.0 (C-40); 70.1 (C-30);
60.3 (C-50); 37.1 (C-20); 11.1 (C4-Me). Anal. calc. for C21H22ClSN3O3 (431.9):

306
Al-Masoudi et al.
C, 58.39; H, 5.13; N, 9.73. Found: C, 58.13; H, 5.02.; N, 9.58. MS: m=z (FAB)
474=456 (MNa)þ.
2-(2,3,5-Tri-O-benzoyl-b-D-ribofuranosylsulfanyl)-1-(4-chlorophenylamino)-4-
methyl-5-phenyl-1H-imidazole (18). This compound was prepared from condens-
ation of 4 (0.50 g, 1.58 mmol) with 5 (0.87 g, 1.74 mmol), in the similar manner of
preparation of 9. Yield: 0.34 g, (28%); m.p. 85–91ꢀC. dH (CDCl3): 9.20 (s, 1H,
NH); 7.36–7.31 (m, 5H, C5-Ph); 6.37, 6.28 (2d, 2H, J ¼ 8.0 Hz, 4-ClPh); Ar); 6.10
0
0
0
(dd, 1H, J1 ,2 ¼ 5.3 Hz, H-1 ); 6.60, 6.52 (2d, 4H, J ¼ 8.0 Hz, 4-ClPh); 5.56-5.49 (m,
2H, H-20, H-30); 4.56 (dd, 1H, J4 ,5 ¼ 3.0 Hz, H-4 ); 4.32–4.18 (m, 2H, H-5 , H-5 );
2.34 (s, 3H, Me). dC (DMSO-d6): 169.2, 169.0, 168.5 (C ¼ O); 142.5 (C-2); 133.3–
128.8 (Ar); 126.4 (C-5); 120.2 (C-4); 114.5, 112.7 (Ph); 86.6 (C-10); 80.2 (C-40); 74.4
(C-20); 70.5 (C-30); 62.5 (C-50); 11.1 (C4-Me). Anal. calc. for C42H34ClSN3O7
(760.3): C, 66.35; H, 4.51; N, 5.53. Found: C, 66.24; H, 4.43; N, 5.35. MS: m=z
(FAB) 760=762 (MH)þ.
0
0
00
0
00
1-(4-Chlorophenylamino)-4-methyl-5-phenyl-2-(b-D-ribofuranosylsulfanyl)-1H-
imidazole (19). This compound was prepared from 18 (0.50 g, 0.66 mmol), in the
similar manner of preparation of 17. Yield: 0.23 g, (78%); m.p. 178–180ꢀC decom.
dH (CDCl3): 9.25 (s, 1H, NH); 7.41–7.38 (m, 5H, C5-Ph); 7.03, 6.98 (2d, 2H,
0
0
0
J ¼ 8.0 Hz, 4-ClPh); 5.81 (2d, 1H, J1 ,2 ¼ 4.9 Hz, H-1 ); 6.46, 6.38 (2d, 2H, J ¼ 8.0 Hz,
0
0
NH-4-ClPh); 5.84 (t, 1H J ¼ 5.8 Hz, C5 -OH); 5.33 (d, 1H, J ¼ 5.7 Hz, C2 -OH); 5.14
0
0
0
0
(d, 1H, J ¼ 3.7 Hz, C3 -OH); 4.15 (dd, 1H, J2 ,3 ¼ 5.0 Hz, H-2 ); 4.12–3.39 (m, 4H,
H-30-H-500); 2.33 (s, 3H, Me). dC (DMSO-d6): 146.3 (C-2); 134.0–129.5 (Ar); 126,8
(C-5); 120.8 (C-4); 115.2, 113.2 (Ph); 89.6 (C-10); 84.4 (C-40); 74.8 (C-20); 70.9 (C-30);
62.9 (C-50); 11.2 (C4-Me). Anal. calc. for C21H22ClSN3O4(447.9): C, 56.31; H, 4.95;
N, 9.38. Found: C, 56.16; H, 4.87; N, 9.16. MS: m=z (FAB) 471=473 (MNa)þ.
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Received August 27, 2002
Accepted January 27, 2003