Some novel thiopyrimidine nucleoside analogs: Synthesis and in vitro antimicrobial evaluation

Article abstract of DOI:10.1080/00397911003632881

Some new S-alkyl derivatives of indeno[1',2':4,5]thieno[2,3-d]pyrimidine 2-8 were prepared starting with pyrimidine-2(1H)-thione derivative (1). Also, treatment of compound 1 with 2,3,4,6-tetra-O-acetyl - α D-glucopyranosyl bromide or 1-O-acetyl-2,3,5-tri

Full text of DOI:10.1080/00397911003632881

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Some Novel Thiopyrimidine Nucleoside
Analogs: Synthesis and In Vitro
Antimicrobial Evaluation
Aymn E. Rashad a , Ahmed H. Shamroukh a , Hayam H. Sayed b
Samir M. Awad b & Nayera A. M. Abdelwahed c
,
a Photochemistry Department, National Research Center, Cairo,
Egypt
b Organic Chemistry Department, Faculty of Pharmacy, Helwan
University, Cairo, Egypt
c Department of Natural and Microbial Products, National Research
Center, Cairo, Egypt
Published online: 31 Jan 2011.
To cite this article: Aymn E. Rashad , Ahmed H. Shamroukh , Hayam H. Sayed , Samir M. Awad &
Nayera A. M. Abdelwahed (2011): Some Novel Thiopyrimidine Nucleoside Analogs: Synthesis and
In Vitro Antimicrobial Evaluation, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 41:5, 652-661
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Synthetic Communications1, 41: 652–661, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911003632881
SOME NOVEL THIOPYRIMIDINE NUCLEOSIDE
ANALOGS: SYNTHESIS AND IN VITRO
ANTIMICROBIAL EVALUATION
Aymn E. Rashad,1 Ahmed H. Shamroukh,1 Hayam H. Sayed,2
Samir M. Awad,2 and Nayera A. M. Abdelwahed3
1Photochemistry Department, National Research Center, Cairo, Egypt
2Organic Chemistry Department, Faculty of Pharmacy, Helwan University,
Cairo, Egypt
3Department of Natural and Microbial Products, National Research Center,
Cairo, Egypt
Abstract Some new S-alkyl derivatives of indeno[10,20:4,5]thieno[2,3-d]pyrimidine 2–8
were prepared starting with pyrimidine-2(1H)-thione derivative (1). Also, treatment of
compound 1 with 2,3,4,6-tetra-O-acetyl-a-D-glucopyranosyl bromide or 1-O-acetyl-2,3,5-
tri-O-benzoyl-b-D-ribofuranose afforded nucleosides 9 and 12, respectively. Furthermore,
deprotection of the latter blocked nucleosides was achieved in methanolic ammonia to afford
the desired free S-nucleoside derivatives 10 and 13, respectively. Some prepared products
were screened for antimicrobial activity, and some of them showed promising activity.
Keywords Acyclic and cyclic nucleosides; antimicrobial activity; indenothieno[2,3-d]pyr-
imidines; S-alkyl derivatives
INTRODUCTION
The pyrimidine ring system undoubtedly belongs to the most important
heterocycles in nature, as it represent the main structure of many biologically signifi-
cant compounds, including nucleosides and nucleotides.[1–3] For this reason, many
analogs and derivatives of pyrimidines have been synthesized and developed as
pharmacologically active compounds or drugs.[4–6] In particular, the chemistry of
Received October 8, 2009.
Address correspondence to Aymn E. Rashad, Photochemistry Department, National Research
Center, Dokki, Cairo, Egypt. E-mail: aymnelzeny@yahoo.com
652

THIOPYRIMIDINE NUCLEOSIDE ANALOGS
653
pyrimidine nucleosides, the main building constituents of DNA and RNA and the
basis of many biological active compounds, has been extensively reviewed,[7–9] and some
acyclic and cyclic nucleosides were reported to be potent antiherpatic drugs with selective
activity against herpes simplex virus (HSV-1 and HSV-2)[10] and hepatitis B virus (HBV)
with mild cytotoxicity.[11] Also, they were reported as potential leishmaniostatic agents[12]
and showed high selectivity against human immunodeficiency virus (HIV-1).[13] More-
over, fused pyrimidine nucleosides have potential antimicrobial,[14] anticancer,[15] and
anti-inflammatory activities.[16] However, there is still a great need to prepare more active
acyclic and cyclic pyrimidine nucleosides with fewer side effects than those observed for
the already known derivatives. Thus, in continuation of our previous work on the syn-
thesis of biologically active fused pyrimidine nucleoside derivatives,[17–21] we aimed to
synthesize some acyclic and cyclic nucleosides related to thioindeno[10,20:4,5]thieno
[2,3-d]pyrimidine derivatives with promising antimicrobial activity.
RESULTS AND DISCUSSION
Recently, our research group prepared some indeno[10,20:4,5]thieno
[2,3-d]pyrimidine derivatives with promising antimicrobial activity,[22] which
prompted us to select one of these active compounds to be the key compound in this
report, treat it with some alkylating reagents and cyclic sugars to get the correspond-
ing acyclic and cyclic nucleosides, and observe the effect on the antimicrobial
activity. Thus, when the sodium salt of compound 1[22] (generated in situ) was
coupled with benzyl bromide, 2-bromoethyl methyl ether, 2-chloroethyl ethyl ether,
or 2-bromoethanol, it afforded the corresponding S-alkyl derivatives 2–5, respect-
ively (Scheme 1). The structures of these products were confirmed with elemental
and spectral data. In particular, the 13C NMR spectra of the latter compounds
revealed the site of attack to be on the sulfur and not on the nitrogen in view of
=
the disappearance of the C S signal.
On the other hand, when compound 5 was treated with acetic anhydride–
glacial acetic acid (3:1) or p-toluene sulfonyl chloride, it gave products 6 and 7,
1
respectively (Scheme 1). The infrared (IR) and H NMR spectra for the latter com-
pounds revealed the absence of the hydroxyl group and the presence of acetyl and
tolyl groups, respectively. In addition, when compound 7 was treated with sodium
azide, it gave the corresponding 2-S-azidoethyl derivative 8, and its IR spectrum
1
showed characteristic absorption bands corresponding to the azide group. Its H
NMR spectrum gave signals at d 3.70 and 4.20 ppm for the S-ethyl carbons.
In recent reports from our laboratory, we described the preparation of some
novel functionalized azine thioglycosides with promising biological activities.[15,23]
These common features encouraged us to develop a new straightforward route for
the synthesis of heterocyclic thieno[2,3-d]pyrimidine thioglycosides. Thus, when
the potassium salt of compound 1[22] (generated in situ) was coupled with
2,3,4,6-tetra-O-acetyl-a-D-glucopyranosyl bromide, it afforded the corresponding
thioglycoside 9 (Scheme 2). The IR spectrum for compound 9 revealed the absence
1
=
=
of the NH and C S groups, as well as the presence of C O signals. Also, the H
NMR spectrum of the latter compound gave a doublet signal characteristic for
the anomeric proton of the glucose moiety at d 6.30 with spin–spin coupling constant
of 9.99 Hz, which corresponds to the diaxial orientation of the H-10 and H-20

654
A. E. RASHAD ET AL.
Scheme 1. Synthesis routes of compounds 2–8.
protons, indicating the presence of the b-configuration,[15,23] while the four acetoxy
groups appear as four singlets in the 1.90–2.20 ppm region.
Deprotection of 9 with ammonia in methanol afforded the free thioglycoside 10
obtained in almost quantitative yield (Scheme 2). The structure of the latter
compound has been established on the basis of elemental analysis and spectral data.
1
Thus, the H NMR spectrum showed the anomeric proton as a doublet at d 6.72 (J
9.30 Hz) indicative for the b-D-configuration. The signals of the other six glucose
protons appear as multiplets at d 3.40–4.35, while the signals of the four hydroxyl
groups of the glucose moiety are observed at d 4.52–5.34 (exchangeable by D2O).
13
=
The C NMR spectrum of 10 is characterized by the disappearance of the C S
signal and the presence of a signal at d 82.44 corresponding to the C-10 atom of b-
D-glucopyranose. Another five signals at d 61.63, 67.64, 69.89, 72.86, and 74.81
are assigned to C-60, C-40, C-20, C-30, and C-50, respectively.
On the other hand, heating of compound 1 with hexamethyldisilazane
(HMDS) in the presence of ammonium sulfate gave the corresponding 2-trimethyl-
silylthiopyrimidine derivative 11, which was subsequently treated with 1-O-
[24]
acetyl-2,3,5-tri-O-benzoyl-b-D-ribofuranose in the presence of SnCl4
to afford
the corresponding S-nucleoside 12 (Scheme 2). The 1H NMR spectrum of 12 showed

THIOPYRIMIDINE NUCLEOSIDE ANALOGS
655
Scheme 2. Synthesis routes of compounds 9–13.
0
0
a doublet at d 5.47 ppm (J1 ,2 ¼ 5.60 Hz) assigned to the anomeric proton indicating
13
the b-configuration,[24] and the other sugar protons resonate at d 4.14–4.88 ppm. In
=
addition, its C NMR spectrum revealed the disappearance of the C S signal and
the presence of a signal at d 92.05 corresponding to the C-10 atom.
Debenzoylation of the blocked nucleoside 12 was achieved in methanolic
ammonia at 0 ꢀC to afford the desired (1-b-D-ribofuranosyl)thieno[2,3-d]pyrimidine
derivative 13. The IR and H NMR spectra of the latter compound showed the
I
presence of hydroxyl groups, and the 13C NMR spectrum provided further
verification of the structure.
Antimicrobial Activity
The in vitro antimicrobial activity of the synthesized compounds was investigated
against several pathogenic representatives of Gram-positive bacteria (Bacillus subtilis),
Gram-negative bacteria (Escherichia coli), fungi (Aspergillus niger), and yeast (Candida

656
A. E. RASHAD ET AL.
albicans). All microorganisms were obtained from the culture collection of the
Department of Natural and Microbial Products, National Research Center, Dokki,
Cairo, Egypt.
Method[25]
The cap-assay method containing (g=L) peptone 6, yeast extract 3, meat extract
1.50, glucose 1, and agar 20 were used. The medium was sterilized and divided while
hot (50–60ꢀC) in 15-mL portions among sterile Petri dishes 9 cm in diameter. One
mL of the spore suspension of each microorganism was spread all over the surface of
the cold solid medium placed in the Petri dish. Each of the tested compounds (0.50g)
was dissolved in 5 mL of dimethylformamide. An amount of 0.10 mL of test solution
was placed on a Whatman paper disc 9 mm in diameter, and the solvent was left to evap-
orate. These saturated discs were placed carefully on the surface of the inoculated solid
medium; each Petri dish contained at least three discs. The Petri dishes were incubated at
5 ꢀC for an hour to permit good diffusion, transferred to an incubator at 85 ꢀC over-
night, and then examined. The results were then recorded by measuring the inhibition
zone diameters. Dimethylsulfoxide (DMSO) as a solvent showed no inhibition zones.
The results were compared to streptomycin and fusidic acid as reference drugs.
RESULTS
As shown in Table 1, the in vitro antimicrobial activity of the tested
compounds was evaluated by measuring the zone diameters, and the results were
Table 1. Antimicrobial activity of some prepared compounds
Disc diffusion test (mm)
Microorganisms
Bacteria
Tested compound nos. and standards Gram negative Gram positive
(mg=mL - lot. no., bioanalyse)
Fungi Yeast
Aspergillus niger C. albicans
E. coli
B. subtilis
Streptomycin (10-30225)
Fusidic acid (10-30301)
þþ
ꢁ
þþ
ꢁ
þ
þþþ
þ
þþþ
þþþ
þþþ
þþ
2
3
þ
þþ
þ
þ
þ
4
þþþ
þ
þþ
þþ
þþ
þþ
þþ
þþ
þ
ꢁ
þþþ
þþþ
þþþ
þþþ
þþ
5
þ
6
þ
ꢁ
7
þ
ꢁ
8
þ
ꢁ
9
þþ
þ
þ
þþ
10
12
13
ꢁ
þ
þþþ
þ
þþ
þ
þþ
ꢁ
þþþ
þþ
þþþ Highly sensitive (21–25 mm); þþ Fairly sensitive (16–20 mm); þ Slightly sensitive (15–10 mm);
ꢁ Not sensitive (0–5 mm).

THIOPYRIMIDINE NUCLEOSIDE ANALOGS
657
compared with those of well-known drugs (standards). Among the tested com-
pounds, it was noticed that the blocked cyclic nucleosides of thieno[2,3-d]pyrimidine
derivative 9 and 12 revealed more significant antimicrobial activities than the S-alkyl
derivatives 2–8, and the unblocked cyclic nucleosides of thieno[2,3-d]pyrimidine
derivatives 10 and 13. In general, the blocked five-member cyclic nucleoside of
thieno[2,3-d]pyrimidine derivative [(2,3,5-tri-O-benzoyl-b-D-ribofuranosyl)thieno
[2,3-d]pyrimidine derivative 12] showed the greatest antimicrobial activity of the
tested compounds and the reference drugs (standards).
EXPERIMENTAL
All melting points were uncorrected and measured using an Electrothermal IA
9100 apparatus (Shimadzu, Kyoto, Japan). IR spectra were recorded as potassium
bromide pellets on a Perkin-Elmer 1650 spectrophotometer (Shimadzu, Japan).
1H NMR and 13C NMR spectra were recorded on Varian Gemini 180 spectrometer
(Varian, Oxford, UK), and chemical shifts were expressed as parts per million (ppm)
against tetramethylsilane (TMS) as internal reference. Mass spectra were recorded
on a GC Ms-QP 1000 EX (Shimadzu, Japan) instrument. Microanalyses were per-
formed an a Vario El Elementar apparatus by the Organic Microanalysis Section,
National Research Center, and gave satisfactory values within a range of ꢂ0.30%
of the calculated values. Chromatography was performed on silica gel 60 (particle
size 0.06–0.20 mm, Merck, Darmstadt, Germany).
Compound 1 was prepared according to a reported method.[22]
General Procedure for the Synthesis of Compounds 2–5
Compound 1 (1 mmol) was added to a solution of dry ethanol (20 mL) contain-
ing KOH (1 mmol), and the reaction mixture was stirred at room temperature for
1 h. Then benzyl bromide, 2-bromoethyl methyl ether, 2-chloroethyl ethyl ether, or
2-bromoethanol (2 mmol) was added, and the reaction mixtures were stirred at
70 ꢀC for 2, 4, 3, and 5 h, respectively. The reaction mixtures were evaporated under
reduced pressure, and the residues were recrystallized from ethanol to give products
2–5, respectively.
Selected Data
2-(2-Benzylsulfanyl)-3-phenyl-3,9-dihydroindeno[1’,2’:4,5]thieno[2,3-d]
1
pyrimidine (2). Yield 89%; mp 160–162 ꢀC; IR (KBr, n, cmꢁ1): 1665 (CO); H
NMR (CDCl3, d ppm): 3.63 (s, 2H, CH2), 4.54 (s, 2H, CH2), 7.33–7.39 (m, 14H,
Ar-H); 13C NMR (CDCl3, d ppm): 35.61 (C-9), 65.75 (CH2), 127.01–154.12
(Ar-C), 160.50 (CO); MS, m=z (%): 436 (Mþ, 100).
2-(2-Methoxyethylsulfanyl)-3-phenyl-3,9-dihydroindeno[1’,2’:4,5]thieno
[2,3-d]pyrimidine (3). Yield 70%; mp 180–182 ꢀC; IR (KBr, n, cmꢁ1): 1696 (CO);
1H NMR (CDCl3, d ppm): 3.34 (s, 2H, CH2), 3.40 (s, 3H, OCH3), 3.50 (t, J ¼ 8.20 Hz,
Hz, 2H, CH2), 4.20 (t, J ¼ 8.20 Hz, 2H, CH2), 7.10–7.50 (m, 9H, Ar-H); 13C NMR

658
A. E. RASHAD ET AL.
(CDCl3, d ppm): 38.53 (C-9), 58.71 (SCH2), 62.78 (OCH3), 70.73 (OCH2),
121.56–150.90 (Ar-C), 158.34 (CO); MS, m=z (%): 406 (Mþ, 84).
2-(2-Ethoxyethylsulfanyl)-3-phenyl-3,9-dihydroindeno[1’,2’:4,5]thieno
[2,3-d]pyrimidine (4). Yield 59%; mp 250–252 ꢀC; IR (KBr, n, cmꢁ1): 1643 (CO);
1H NMR (CDCl3, d ppm): 1.16 (t, J ¼ 6.0 Hz, 3H, CH3), 2.86 (q, t, J ¼ 5.60 Hz, 2H,
CH2), 3.42–3.84 (m, 6H, 3CH2), 7.24–7.54 (m, 9H, Ar-H); 13C NMR (CDCl3, d
ppm): 14.89 (OCH2CH3), 38.43 (C-9), 53.69 (SCH2), 66.11 (OCH2CH3), 68.50
(CH2O), 120.48–150.36 (Ar-C), 158.34 (CO); MS, m=z (%): 420 (Mþ, 92).
2-(2-Hydroxyethylsulfanyl)-3-phenyl-3,9-dihydroindeno[1’,2’:4,5]thieno
[2,3-d]pyrimidine (5). Yield 70%; mp 112–114 ꢀC; IR (KBr, n, cmꢁ1): 3200–3350
1
(OH), 1672 (CO); H NMR (CDCl3, d ppm): 3.27 (s, 2H, CH2), 3.70–3.91 (m, 4H,
2CH2), 4.92 (bs, 1H, OH, D2O exchangeable), 7.01–7.49 (m, 9H, Ar-H); 13C
NMR (CDCl3, d ppm): 30.91 (C-9), 60.32 (CH2), 65.01 (CH2), 120.29–148.86
(Ar-C), 154.52 (CO); MS, m=z (%): 392 (Mþ, 68).
2-(2-Acetoxyethylsulfanyl)-3-phenyl-3,9-dihydroindeno[1’,2’:4,5]thieno
[2,3-d]pyrimidine (6). Compound 5 (1 mmol) was refluxed in a mixture of acetic
anhydride=glacial acetic acid (30 mL : 10 mL) for 3 h. The reaction mixture was
cooled and poured into ice water, and the formed solid was filtered off, dried, and
recrystallized from ethanol to give compound 6.
1
Yield 96%; mp 230–232 ꢀC; IR (KBr, n, cmꢁ1): 1714 (CO), 1634 (CO); H
NMR (CDCl3, d ppm): 2.06 (s, 3H, CH3), 3.44 (s, 2H, CH2), 4.23–4.31 (m, 4H,
2CH2), 7.09–7.58 (m, 9H, Ar-H); 13C NMR (CDCl3, d ppm): 26.57 (CH3), 37.19
(C-9), 56.64 (CH2), 66.40 (CH2), 120.16–148.48 (Ar-C), 152.53 (CO), 158.19 (CO);
MS, m=z (%): 434 (Mþ, 100).
2-(2-p-Tolylsulfonyloxyethylsulfanyl)-3-phenyl-3,9-dihydroindeno[1’,2’:
4,5]thieno[2,3-d]pyrimidine (7). p-Toluenesulfonyl chloride (1 mmol) was added
to an ice-cooled solution of compound 5 (1 mmol) in dry pyridine (20 mL), and
the reaction mixture was stirred at room temperature for 6 h, poured onto ice, and
neutralized with two or three drops of concentrated hydrochloric acid (35%). The
formed precipitate was filtered off, dried, and recrystallized from dioxane to give
compound 7.
Yield 92%; mp 260–262 ꢀC; IR (KBr, n, cmꢁ1): 1174 (C-O-SO2), 1696 (CO); 1H
NMR (CDCl3, d ppm): 2.41 (s, 3H, CH3), 3.67 (s, 2H, CH2), 3.71 (t, J ¼ 6.0 Hz, 2H,
CH2), 4.20 (t, J ¼ 6.0 Hz, 2H, CH2), 7.09–7.55 (m, 9H, Ar-H), 8.26 (d, J ¼ 6.80 Hz,
2H, tolyl-H), 8.59 (d, J ¼ 5.40 Hz, 2H, tolyl-H); 13C NMR (CDCl3, d ppm): d
26.57 (CH3), 39.26 (C-9), 56.85 (CH2), 65.90 (CH2), 120.25–150.12 (Ar-C), 164.29
(CO); MS, m=z (%): 546 (Mþ, 52).
2-(2-Azidoethylsulfanyl)-3-phenyl-3,9-dihydroindeno[1’,2’:4,5]thieno[2,
3-d]pyrimidine (8). A mixture of compound 7 (1 mmol) and sodium azide (1 mmol)
was heated in dry DMF (20 mL) at 80 ꢀC for 3 h. The reaction mixture was evapo-
rated under reduced pressure, and the residue was recrystallized from ethanol to
give 8.
Yield 91%; mp 210–212 ꢀC; IR (KBr, n, cmꢁ1): 2210 (N3), 1696 (CO); 1H NMR
(CDCl3, d ppm): 3.45 (s, 2H, CH2), 3.70 (t, J ¼ 5.0 Hz, 2H, CH2), 4.20 (t, J ¼ 5.0 Hz,

THIOPYRIMIDINE NUCLEOSIDE ANALOGS
659
2H, CH2), 7.10–7.50 (m, 9H, Ar-H); 13C NMR (CDCl3, d ppm): 34.15 (C-9), 69.90
(CH2), 76.54 (CH2), 122.80–153.90 (Ar-C), 158.60 (CO).
3-Phenyl-2-(2’,3’,4’,6’-tetra-O-acetyl-b-D-glucopyranosylsulfanyl)-3,9-
dihydro-indeno[1’,2’:4,5]thieno[2,3-d]pyrimidine (9). A solution of 2,3,4,6-
tetra-O-acetyl-a-D-glucopyranosyl bromide (1 mmol) in dry acetone (10 mL) was
added to a solution of compound 1 (1 mmol) in dry acetone (20 mL) containing
KOH (1 mmol), and the reaction mixture was stirred for 2 h and evaporated under
reduced pressure at 40 ꢀC. The residue was purified on a silica-gel column using
n-hexane=ethyl acetate (4:1) as an eluent to give 9.
1
Yield 56%; mp 235–237 ꢀC; IR (KBr, n, cmꢁ1): 1680, 1715 (CO). H NMR
(CDCl3, d ppm): 1.90–2.20 (4 s, 12H, 4CH3CO), 3.49 (s, 2H, CH2), 4.12–4.30 (m,
4H, CH2 and 60-H2)0, 5.20–5.60 (m, 4H, 50-H, 40-H, 30-H, and 20-H), 6.30 (d,
J1 ,2 ¼ 9.99 Hz, 1H, 1 -H), 7.20–7.50 (m, 9H, Ar H); 13C NMR (CDCl3, d ppm):
20.60–20.73 (4CH3), 34.72 (C-9), 61.68 (C-60), 67.99 (C-40), 69.49 (C-20), 74.13
(C-30), 74.81 (C-50), 85.98 (C-10), 128.17–129.50 (Ar-C), 164.15, 169.34, 169.54,
169,93. 170,54 (5CO).
0
0
3-Phenyl-2-(b-D-glucopyranosylsulfanyl)-3,9-dihydroindeno[1’,2’:4,5]
thieno[2,3-d]pyrimidine (10). Ammonium hydroxide solution (3 mL, 35%) was
added to a solution of dry methanol (20 mL) containing 1 mmol of compound 9,
and then the reaction mixture was stirred at room temperature for 5 h and evapo-
rated under reduced pressure at 40 ꢀC. The residue was purified on a silica-gel
column using chloroform=methanol (4:1) as an eluent to give 10.
1
Yield 74%; oil; IR (KBr, n, cmꢁ1): 3500–3200 (OH), 1685 (CO); H NMR
(CDCl3, d ppm): 3.24 (s, 2H, CH2), 3.40–3.60 (m, 3H, 60-H2, H-50), 4.10–4.35 (m,
3H, H-40, H-30, and H-20), 4.52 (m, 1H, OH, D2O exchangeable), 5.03 (m, 1H,
OH, D2O exchangeable), 5.17 (m, 1H, OH, D2O exchangeable), 5.34 (m, 1H, OH,
0
0
0
D2O exchangeable), 6.72 (d, J1 ,2 ¼ 9.30 Hz, 1H, H-1 ), 7.20–7.35 (m, 9H, Ar-H);
13C NMR (CDCl3, d ppm): 35.12 (C-9), 61.63 (C-60), 67.64 (C-40), 69.89 (C-20),
72.86 (C-30), 74.81 (C-50), 82.44 (C-10), 128.17–129.50 (Ar-C).
2-(2’,3’,5’-Tri-O-benzoyl-b-D-ribofuranosyl)-3-phenyl-3,9-dihydroindeno
[1’,2’:4,5]thieno[2,3-d]pyrimidine (12). Compound 1 (1 mmol) was refluxed by
stirring under anhydrous condition for 12 h with hexamethyldisilazane (60 mL)
and ammonium sulfate (0.02 g). The clear solution obtained was cooled, and the
solvent was removed under reduced pressure. The resulting trimethylsilylated
pyrimdine 11 was dissolved in dry 1,2-dichloromethane (40 mL), and a solution of
1-O-acetyl-2,3,5-tri-O-benzoyl-b-D-ribofuranose (1 mmol) and SnCl4 (1.6 mL) in
dry 1,2-dichloromethane (10 mL) was then added dropwise with stirring under an
inert atmosphere (nitrogen gas) until the reaction was judged complete by thin-layer
chromatography (TLC, 5 h). Then the reaction mixture was poured into saturated
NaHCO3 solution and extracted with CHCl3 (2 ꢃ 30 mL). The extract was collected,
dried over Na2SO4, filtered, and concentrated to give the crude nucleoside, which
was purified on a silica-gel column using n-hexane = ethyl acetate (4:1) as an eluent
to give 12.
1
Yield 48%; mp 184–186 ꢀC; IR (KBr, n, cmꢁ1): 1720, 1670 (CO); H NMR
(CDCl3, d ppm): 3.69 (s, 2H, CH2), 4.14 (m, 1H, 40-H), 4.39 (m, 2H, 50-H2),

660
A. E. RASHAD ET AL.
0
4.68–4.88 (m, 2H, 20-H, 30-H), 5.47 (d, J1 ,2 ¼ 5.60 Hz, 1H, 1 -H), 6.50–6.80 (m, 4H,
0
0
13
Ar-H), 7.10–7.96 (m, 20H, Ar-H). C NMR (CDC13): 33.56 (C-9), 63.12 (C-50),
70.30 (C-30), 72.54 (C-20), 79.85 (C-40), 92.05 (C-l0), 115.26–150.15 (Ar-C), 158.47,
165.49, 166.21, 166.48 (4 CO).
3-Phenyl-2-(1-b-D-ribofuranosyl)-3,9-dihydroindeno[1’,2’:4,5]thieno[2,3-d]
pyrimidine (13). Dry ammonia gas was passed into a solution of protected nucleo-
sides 12 (1 mmol) in dry methanol (20 mL) at 0 ꢀC for 0.5 h, then the reaction mixture
was stirred at room temperature until the reaction was judged complete by TLC
(12 h). The resulting mixture was then concentrated under reduced pressure at
40 ꢀC to afford a solid residue, which was purified on a silica-gel column using
chloroform=methanol (4:1) as an eluent to give 13.
Yield 54%; oil; IR (KBr, n, cmꢁ1): 3440 (OH), 1660 (CO); 1H NMR (CDCl3, d
ppm): 3.53 (s, 2H, CH2), 3.81–4.28 (m, 3H, 40-H, 50-H2), 4.44–4.65 (m, 20-H, 30-H),
4.82 (m, 1H, OH, D2O exchangeable), 4.95 (m, 1H, OH, D2O exchangeable), 5.15
0
0
0
(m, 1H, OH, D2O exchangeable), 5.42–5.44 (d, 1H, J1 ,2 ¼ 5.20 Hz, 1 -H), 7.11–7.46
13
(m, 9H, Ar-H); C NMR (CDCl3, d ppm): 35.12 (C-9), 64.22 (C-50), 72.86 (C-30),
75.24 (C-20), 81.35 (C-40), 90.05 (C-l0), 115.52–150.15 (Ar-C), 158.47 (CO).
ACKNOWLEDGMENT
We are grateful to Deutsche Forschungsgemeinschaft (DFG) and Prof. Klaus
Banert, Chemistry Department, Technical University, Chemnitz, Germany, for
facilities and support.
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