Simple analogues of acyclonucleosides: Synthesis of N-substituted pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine derivatives

Article abstract of DOI:10.1080/00397910600767181

The synthesis of N-substituted pyridothienopyrimidines bearing ethoxymethyl, benzyloxymethyl, methylthiomethyl, benzoylmethyl, allyl, sec-butyl, and 2-acetyloxyethyl chains as a sugar mimic was described. The O-substituted pyridothienopyrimidines were obt

Full text of DOI:10.1080/00397910600767181

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Simple Analogues of Acyclonucleosides: Synthesis of
N‐Substituted Pyrido[3′,2′:4,5]thieno[3,2‐d]pyrimidine
Derivatives
Ahmed F. Khattab a , Magdy A. Zahran a & Ahmed Saif b
a Chemistry Department, Faculty of Science , Monoufiya University , Shebien El‐Koam, Egypt
b Sugar and Integrated Industries Company , El‐Hawamdiya, Egypt
Published online: 16 Feb 2007.
To cite this article: Ahmed F. Khattab , Magdy A. Zahran & Ahmed Saif (2006) Simple Analogues of Acyclonucleosides:
Synthesis of N‐Substituted Pyrido[3′,2′:4,5]thieno[3,2‐d]pyrimidine Derivatives, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 36:19, 2751-2761, DOI: 10.1080/00397910600767181
To link to this article: http://dx.doi.org/10.1080/00397910600767181
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Synthetic Communicationsw, 36: 2751–2761, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600767181
Simple Analogues of Acyclonucleosides:
Synthesis of N-Substituted
Pyrido[30,20:4,5]thieno[3,2-d]pyrimidine
Derivatives
Ahmed F. Khattab and Magdy A. Zahran
Chemistry Department, Faculty of Science, Monoufiya University,
Shebien El-Koam, Egypt
Ahmed Saif
Sugar and Integrated Industries Company, El-Hawamdiya, Egypt
Abstract: The synthesis of N-substituted pyridothienopyrimidines bearing
ethoxymethyl, benzyloxymethyl, methylthiomethyl, benzoylmethyl, allyl, sec-butyl,
and 2-acetyloxyethyl chains as a sugar mimic was described. The O-substituted pyri-
dothienopyrimidines were obtained during some reactions.
Keywords: Acyclonucleosides, alkylation, pyridothienopyrimidines
Acyclonucleosides are a group of nucleosides that differ from the ribonucleo-
sides in only the sugar portion. The general feature of the important members
of this class of nucleosides is the absence of one or more bonds of the pentose
moiety, giving an open chain residue. They possess portions of the pentose
residue. Those nucleosides missing one bond of the furanosyl residue
are called seco-nucleosides. The terms diseco-, triseco-, tetraseco, and
pentaseco-nucleoside are given by El Ashry and El Kilany.[1–3] Acyclo-
nucleosides analogs of the tricyclic system represent an important group of
biologically active molecules.[4–6] Pyridothienopyrimidines are versatile
Received in the U.K. October 7, 2005
Address correspondence to Ahmed F. Khattab, Chemistry Department, Faculty of
Science, Monoufiya University, Shebien El-Koam, Egypt. E-mail: khattab2000@
yahoo.com
2751

2752
A. F. Khattab, M. A. Zahran, and A. Saif
examples of a triheterocyclic system. They attracted much attention because
of their interesting biological activities.[7–9] It has been found that the
3-alkyl, 3-alkylthioalkyl, and 4-alkoxypyridothienopyrimidines enhance
analgesic, anesthetic, anti-anaphylactic, anti-inflammatory, and antipyretic
activities.[10–13] Such derivatives have been prepared through different
routes.[11–16] In the present work, as a continuation of our interest in this
area,[17] we report a simple route via alkylation to pyridothienopyrimidines
for the synthesis of a new series of acyclonucleoside analogues to gain
further biological activity.
RESULTS AND DISCUSSION
The starting pyridothienopyrimidine derivative 1 was prepared by conden-
sation of ethyl 2-amino thienopyridine-3-carboxylates with formamide using
the method described by Shvedov and coworkers.[18] The reaction of 1 with
either chloromethyl ethyl ether 2a or benzyl chloromethyl ether 2b, by the
method of Sasaki et al.,[19] afforded the corresponding N-3 and N-1 substituted
products, 3a,b and 4a,b respectively. These mixed products could be
separated by using ethyl acetate and chloroform (0–5%) in column chromato-
graphy to give 3 and 4 in 6–57% yields. The infrared spectra of compounds
3a, 3b, 4a and 4b showed absorption bands of carbonyl group at 1680,
1684, 1682, and 1677 cm21, respectively. This indicates that alkylation had
not occured at the oxygen atom but occurred at N-1 and N-3 to give the
N-alkylated products. The 1H NMR spectrum of 3a showed a triplet at
1.22 ppm corresponding to the CH3 group, two singlets at 2.66 and
2.90 ppm corresponding to two methyl groups, a quartet at 3.62 ppm corre-
sponding to a CH2 group, a singlet at 5.60 ppm corresponding to a CH2
group, and two singlets at 7.07 and 8.27 ppm corresponding to C8-H and
1
C2-H, respectively. In its H NMR spectrum, compound 4a showed almost
1
similar data. Similarly, H NMR spectra of compounds 3b and 4b showed
almost similar data, and consequently the compounds cannot be differentiated
by 1H NMR spectroscopy. However, 13C NMR spectra showed the chemical
shift of C-1 of the acyclic part of 4a,b at 74.85 and 74.43 ppm whereas for that
of compound 3a,b, the shift showed at 72.75 and 73.1 ppm. This in agreement
with the recently reported data[20] that the 13C NMR spectra showed C-1 of the
acyclic of N-1 shifted downfield compared with that of N-3 in pyrimidine ring.
On the other hand, reaction of 1 with either chloromethyl methylsulfide or
phenacyl bromide, under the same reaction conditions, afforded N-3 sub-
stituted products 3c and 3d as sole products (Scheme 1). 1H NMR and
13C NMR spectra were not decisive for the elucidation of the site of substi-
tution. An absolute proof of the structure was achieved by X-ray analysis
of compound 3c. It shows that the substitution took place in N-3 rather than
N-1 (Fig. 1). Crystal structure has been deposited at the Cambridge Crystallo-
graphic Data Centre and allocated the deposition number CCDC 273385;

Analogues of Acyclonucleosides
2753
Scheme 1.
e-mail: deposit@ccdc.cam.ac.uk and CCDC home page: http:// www.ccdc.cam.
ac.uk. Crystallographic data for 3c: chemical formula: C13H13N3OS2; formula
weight, 291.359; temperature (K), 298; crystal system, monoclinic; space
˚
˚
group, C2/c; unit cell dimension, a ¼ 24.5663(14) A, b ¼ 8.9730(5) A, c ¼
3
˚
˚
14.2017(7) A, a ¼ 90.008, b ¼ 120.450(8)8, g ¼ 90.008; volume, 2696.2(3) A .
˚
Figure 1. Crystal structure of 3c: Selected bond length (A) and bond angles (8):
S(1)–C(11) 1.801(8), S(1)–C(19) 1663(7), N(7)–C(13) 1.432(9), N(7)–C(14)
1.410(9), S(2)–C(3) 1.768(8), S(2)–C(13) 1788(8), N(8)–C(14) 1.299(9), N(8)–
C(12) 1.368(9), C(17)–O(21) 1.249(8), C(11)–S(1)–C(19) 99.3, C(13)–N(7)–C(17)
122.8, C(13)–N(7)–C(14) 112.8(7), C(3)–S(2)–C(13) 92.6(4), N(8)–C(12)–C(15)
96.5(5), C(15)–C(9)–C(18) 130.2(7), S(2)–C(13)–N(7) 123.2(7), N(7)–C(14)–
N(8) 115.0(5), N(4)–C(16)–C(20) 32.2(3), N(4)–C(16)–C(11) 117.6(8).

2754
A. F. Khattab, M. A. Zahran, and A. Saif
Whereas reaction of 1 with allyl chloride or 2-bromobutane and/or
2-bromoethyl acetate under the same reaction conditions furnished two
products (by thin-layer chromography, TLC), which could be separated by
using ethyl acetate in chloroform (0–5%) in the column chromatography to
give N-alkylated products 6a–c and O-alkylated products 7a–c in 24–59%
yields.
1
The H NMR spectra showed that the acyclic part of the O-alkylated
products 7a–c was shifted downfield compared with that of N-alkylated
products 6a–c. For example, the methylene douplet signals appeared at
5.41 ppm for O-alkylated product 7a, compared to 5.35 ppm for N-alkylated
product 6a. The sites of alkylation were confirmed by the 13C NMR spectra
of these compounds, which showed the chemical shift of C-1 of acyclic
part of 6a–c at 48.33, 51.83, and 61.56 ppm, whereas those of compounds
7a–c were at 67.52, 75.09, and 64.63 ppm, respectively. This indicated
that the alkylation of 1 occurred on the nitrogen atom to give 6a–c and on
the oxygen atom to give 7a–c. This was also confirmed by the presence
of characteristic IR peaks for carbonyl group at 1657–1673 cm21 of
Scheme 2.

Analogues of Acyclonucleosides
2755
compound 6a–c. The lack of this peak in the IR spectra of compounds 7a–c
and the appearance of a characteristic peak for ether linkage at
1125–1130 cm21 indicate that the alkylation occurred at the oxygen atom
to afford O-alkylated products.
Subsequent treatment of compounds 6c and 7c with a 1:1 mixture of
methanol and concentrated ammonia at room temperature gave the corre-
sponding hydroxy compounds 8 and 9, respectively. The hydroxyl
compound 8 was tosylated by reaction with tosyl chloride in anhydrous
pyridine to give the tosylate 10, which could then be converted, upon
treatment with sodium azide in dry DMF, to the azide 11. This azide has
been shown to be a versatile synthon for a further 1,3-dipolar cycloaddition
reaction. The IR, NMR, mass spectra, and elemental analysis established
the structure of 11. The IR spectrum showed a characteristic band for an
azido group at 2105 cm21 (Scheme 2).
In conclusion, simple alkylation of pyridothienopyrimidine derivative 1
with different alkylating agents by the method of Sasaki et al.[19] afforded
N-3 alkylated products as the sole ones or N-3 alkylated products as the
major products with N-1 alkylated or O-alkylated as minor products.
EXPERIMENTAL
Melting points were determined on a Boetius melting-point apparatus and are
uncorrected. IR spectra were recorded on a Nicolet 250 FT-IR spectropho-
tometer as potassium bromide pellets and expressed as n in centimeters21
.
NMR spectra were recorded at 300 MHz for 1H NMR, 75.5 MHz for
13C NMR on a Varian Gemini 2000 300 spectrometer; d values are in parts
per million (ppm) relative to tetramethylsilane as the internal standard.
Mass spectra (EI, 70 eV) were obtained on a Varian Mat CH-6 spectrometer
and FAB spectra on a Kratos MS 50 RF spectrometer. Elemental analyses
were performed at the Chemistry Institute, Copenhagen University,
Denmark. X-ray calculations were performed, using maXus (Bruker
Nonius, Delft, and MaxScience), at the National Research Center, Dokki,
Cairo, Egypt. The progress of reactions was monitored by TLC (analytical
silica-gel plates 60 F254). Merck silica gel (0.040–0.063 mm) was used for
column chromatography. Solvents for chromatography were distilled prior
˚
to use. N,N-Dimethylformamide was dried over 4-A sieves after distillation.
˚
Pyridine was dried over 4-A sieves.
General Procedure for the Preparation of Compounds (3,4)
To a stirred suspended solution of 1 (1.16 g, 5 mmol) in anhydrous N,N-
dimethylformamide (10 ml), 0.2 g (5 mmol) of sodium hydride (60%
dispersion in mineral oil) was added. After evolution of hydrogen

2756
A. F. Khattab, M. A. Zahran, and A. Saif
was completed (1 h), the appropriate chloromethyl ethyl ether, benzyl
chloromethyl ether, chloromethyl methylsulfide, or phenacyl bromide
(10 mmol) was added dropwise, and the reaction mixture was stirred at
room temperature for 24 h. The solvent was removed under reduced pressure
and the residue co-evaporated with anhydrous toluene (3 ꢀ 10 ml). The
compounds were purified by silica-gel column chromatography with ethyl
acetate in chloroform (0–5%). Fractions with N-1 alkylated derivatives 4a
and 4b were eluted faster than their N-3 alkylated counterparts 3a and 3b.
N-3 Alkylated products 3c and 3d were obtained as sole products.
Data
3-(Ethoxymethyl)-7,9-dimethylpyrido[30,20:4,5]thieno[3,2-d]pyrimidin-
4(3H)-one (3a): Mp 132–1348C (diethyl ether) (56% yield); IR: 1680
(C55O), 1573 (C55N), 1100 (C-O-C); 1H NMR (CDCl3): 1.22 (t, 3H,
J ¼ 7.2 Hz, CH3), 2.66 (s, 3H, CH3), 2.90 (s, 3H, CH3), 3.62 (q, 2H,
J ¼ 7.1 Hz, CH2), 5.60 (s, 2H, CH2), 7.07 (s, 1H, C8-H), 8.27 (s, 1H,
C2-H); 13C NMR (CDCl3): 14.92 (CH3), 19.31 (CH3), 24.52 (CH3), 64.17
(CH2), 72.75 (N-CH2-O), 122.67, 124.38, 147.03, 147.12, 151.95, 57.36,
160.04, 162.99 (C-arom and CO); MS (EI): m/z (%) 289 (Mþ, 2), 245
(100), 231 (35), 202 (20), 59 (35). Anal. calcd. for C14H15N3O2S: C, 58.11;
H, 5.23; N, 14.52. Found: C, 57.88; H, 4.91; N, 14.19.
1-(Ethoxymethyl)-7,9-dimethylpyrido[30,20:4,5]thieno[3,2-d]pyrimidin-
4(1H)-one (4a): Mp 160–1628C (diethyl ether) (17% yield); IR: 1682
(C55O), 1573 (C55N), 1010 (C-O-C); 1H NMR (CDCl3): 1.25 (t, 3H,
J ¼ 3.7 Hz, CH3), 2.66 (s, 3H, CH3), 2.91 (s, 3H, CH3), 3.70 (q, 2H,
J ¼ 7.0 Hz, CH2), 5.54 (s, 2H, CH2), 7.08 (s, 1H, C8-H), 8.28 (s, 1H,
C2-H); 13C NMR (CDCl3): 14.89 (CH3), 19.31 (CH3), 24.52 (CH3), 65.66
(CH2), 74.85 (N-CH2-O), 122.67, 124.40, 147.01, 151.91, 157.64, 160.03,
162.97 (C-arom and CO). MS (EI): m/z (%) 289 (Mþ, 32), 245 (100), 231
(50), 202 (40). Anal. calcd. for C14H15N3O2S: C, 58.11; H, 5.23; N, 14.52.
Found; C, 58.35; H, 4.96; N, 14.58.
3-[(Benzyloxy)methyl]-7,9-dimethylpyrido[30,20:4,5]thieno[3,2-d]pyrimidin-
4(3H)-one(3b): Mp 130–1318C (diethyl ether) (57% yield); IR: 1684
(C55O), 1568 (C55N), 1047 (C-O-C); H NMR (CDCl3): 2.58 (s, 3H, CH3),
1
2.79 (s, 3H, CH3), 4.53 (s, 2H, CH2), 5.52 (s, 2H, CH2), 6.98 (s, 1H, C8-H),
7.18 (m, 5H, arom), 8.12 (s, 1H, C2-H); 13C NMR (CDCl3): 19.30 (CH3),
24.53 (CH3), 70.17 (CH2), 73.1 (CH2), 122.64, 124.39, 127.75, 128.28,
128.38, 136.91, 147.00, 147.05, 151.94, 157.35, 160.03, 162.98 (C-arom
and CO). MS (EI): m/z (%) 351 (Mþ, 1), 320 (20), 275 (30), 245 (95), 231
(25), 215 (30), 91 (100). Anal. calcd. for C19H17N3O2S: C, 64.94; H, 4.88;
N, 11.96. Found: C, 64.67; H, 5.02; N, 12.13.

Analogues of Acyclonucleosides
2757
1-[(Benzyloxy)methyl]-7,9-dimethylpyrido[30,20:4,5]thieno[3,2-d]pyri-
midin-4(1H)-one(4b): Mp 128–1308C (diethyl ether) (6% yield); IR:
1677 (C55O), 1568 (C55N), 1102 (C-O-C); 1H NMR (CDCl3): 2.67
(s, 3H, CH3), 2.91 (s, 3H, CH3), 4.71 (s, 2H, O-CH2Ph), 5.59 (s, 2H,
N-CH2-O), 7.08 (s, 1H, C8-H), 7.32 (m, 5H, Ar-H), 8.26 (s, 1H, C2-H);
13C NMR (CDCl3): 19.34 (CH3), 24.55 (CH3), 72.01 (CH2), 74.43
(CH2), 122.14, 122.71, 124.41, 127.78, 127.89, 128.11, 128.47, 136.52,
146.93, 147.04, 151.93, 157.68, 160.09 (CO), 163.01 (C-arom and CO).
MS (EI): m/z (%) 351 (Mþ, 50), 320 (18), 214 (20), 105 (100). Anal.
calcd. for C19H17N3O2S: C, 64.94; H, 4.88; N, 11.96. Found: C, 65.03;
H, 4.52; N, 11.80.
7,9-Dimethyl-3-[(methylthio)methyl]pyrido[30,20:4,5]thieno[3,2-d]pyri-
midin-4(3H)-one (3c): Mp 176–1788C (diethyl ether) (64% yield); IR: 1671
(C55O), 1564 (C55N); H NMR (CDCl3): 2.27 (s, 3H, CH3), 2.67 (s, 3H,
1
CH3), 2.91 (s, 3H, CH3), 5.18 (s, 2H, CH2), 7.09 (s, 1H, C8-H), 8.31 (s, 1H,
C2-H); 13C NMR (CDCl3): 15.11 (CH3), 19.31 (CH3), 24.55 (CH3), 48.64
(CH2), 122.36, 122.76, 124.04, 146.52, 146.99, 151.70, 157.41, 160.06,
162.96 (C-arom and CO). MS (EI): m/z (%) 291 (Mþ, 80), 276 (15), 245
(100), 232 (60). Anal. calcd for C13H13N3OS2: C, 53.58; H, 4.50; N, 14.42.
Found: C, 53.55; H, 4.27; N, 14.51.
3-Benzoylmethyl-7,9-dimethylpyrido[30,20:4,5]thieno[3,2-d]pyrimidin-4(3H)-
one (3d): Mp 220–2238C (methanol) (71% yield); IR: 1673 (C55O), 1572
(C55N); H NMR (DMSO): 2.62 (S, 3H, CH3), 2.91 (s, 3H, CH3), 5.77
1
(s, 2H, CH2), 7.33 (s, 1H, C8-H), 7.74 (m, 5H, arom), 8.26 (s, 1H, C2-H);
13C NMR (DMSO): 18.84 (CH3), 23.99 (CH3), 52.22 (CH2), 120.21,
122.81, 123.89, 134.07, 134.29, 146.61, 149.92, 152.00, 156.59, 160.06,
161.52 (C-arom and CO). MS (EI): m/z (%) 349 (Mþ, 50), 214 (5), 105
(100). Anal. calcd. for C19H15N3O2S: C, 65.31; H, 4.33; N, 12.03. Found:
C, 65.43; H, 4.22; N, 11.80.
General Procedure for the Preparation of Compounds 6 and 7
Sodium hydride (0.2 g, 5 mmol, 60% dispersed in mineral oil) was added to a
stirred suspended solution of 1 (1.16 g, 5 mmol) in anhydrous N,N-dimethyl-
formamide (10 ml). When liberation of hydrogen had ceased (1 h), the
appropriate halide (10 mmol) was added, and the reaction mixture was
stirred at room temperature for 24 h. The solvent was removed under
reduced pressure, the residue was co-evaporated with anhydrous toluene
(3 ꢀ 10 ml), and the compounds were purified by silica-gel column
chromatography with ethyl acetate in chloroform (0–5%). Fractions with
O-alkylated derivatives 7a, 7b, and 7c were eluated faster than their
N-alkylated counterparts 6a, 6b, and 6c.

2758
A. F. Khattab, M. A. Zahran, and A. Saif
Data
3-Allyl-7,9-dimethylpyrido[30,20:4,5]thieno[3,2-d]pyrimidin-4(3H)-one (6a):
Mp 190–1928C (diethyl ether) (59% yield); IR: 1657 (C55O), 1574
(C55N); 1H NMR (CDCl3): 2.68 (s, 3H, CH3), 2.91 (s, 3H, CH3), 4.74
(dd, 2H, J1 ¼ 1.3 Hz, J2 ¼ 4.7 Hz, CH2), 5.35 (dd, 2H, J1 ¼ 0.9 Hz,
J2 ¼ 2.3 Hz, CH2), 6.03 (m, 1H, CH), 7.08 (s, 1H, C8-H), 8.16 (s, 1H,
C2-H); 13C NMR (CDCl3): 19.26 (CH3), 24.51 (CH3), 48.33 (CH2), 119.36,
121.49 (-CH55CH2), 122.59, 124.40, 131.63, 146.88, 146.90, 51.91, 157.22,
159.88, 162.86 (C-arom and CO). MS (EI): m/z (%) 271 (Mþ, 40), 256
(30), 214 (10), 175 (20), 131 (20), 41(100). Anal. calcd. for C14H13N3OS:
C, 61.97; H, 4.83; N, 15.49. Found: C, 62.06; H; 4.69; N, 15.25.
4-(Allyloxy)-7,9-dimethylpyrido[30,20:4,5]thieno[3,2-d]pyrimidine (7a): Mp
1
124–1268C (diethyl ether) (28% yield); IR: 1575 (C55N), 1125 (C-O-C); H
NMR (CDCl3): 2.68 (s, 3H, CH3), 3.01 (s, 3H, CH3), 5.12 (d, 2H, J ¼ 1.2 Hz,
CH2), 5.41 (dd, 2H, J1 ¼ 1.2 Hz, J2 ¼ 4.4 Hz, CH2), 6.10–6.23 (m, 1H, CH),
8.84 (s, 1H, C2-H), 7.11 (s, 1H, C8-H), 13C NMR (CDCl3): 19.61 (CH3),
24.56 (CH3), 67.52 (O-CH2), 116.39, 118.64 (-CH55CH2); 122.54, 23.73,
132.11, 147.30, 153.94, 157.76, 160.41, 162.63, 163.58 (C-arom). Anal. calcd.
for C14H13N3OS: C, 61.97; H, 4.83; N, 15.49. Found: C, 62.11; H, 4.74; N,
15.28.
3-sec-Butyl-7,9-dimethylpyrido[30,20:4,5]thieno[3,2-d]pyrimidin-4(3H)-one
(6b): Mp 149–1518C (56% yield); IR: 1673 (C55O), 1572 (C55N); 1H NMR
(CDCl3): 0.98 (t, 3H, J ¼ 7.4 Hz, CH3), 1.53 (d, 3H, J ¼ 6.8 Hz, CH3), 1.75
(m, 2H, CH2), 2.67 (s, 3H, CH3), 2.93 (s, 3H, CH3), 5.08 (m, 1H, CH), 7.08
(s, 1H, C8-H), 8.20 (s, 1H, C2-H), 13C NMR (CDCl3): 10.64 (CH3), 19.22,
19.35 (CH3), 24.50 (CH3), 29.24 (CH2), 51.83 (N-CH), 121.85, 122.53,
124.42, 144.59, 146.76, 15.16, 157.52, 159.74, 162.88 (C-arom and CO). MS
(EI): m/z (%) 287 (Mþ, 40), 231 (100), 202 (15). Anal. calcd. for
C15H17N3OS: C, 62.69; H, 5.96; N, 14.62. Found: C, 62.44; H, 6.12; N, 14.27.
4-sec-Butoxy-7,9-dimethylpyrido[30,20:4,5]thieno[3,2-d]pyrimidine (7b):
1
Mp 103–1058C (29% yield); IR: 1573 (C55N), 1125 (C-O-C), H NMR
(CDCl3): 1.33 (t, 3H, J ¼ 7.5 Hz, CH3), 1.47 (d, 3H, J ¼ 6.5 Hz, CH3),
1.86 (m, 2H, CH2), 2.69 (s, 3H, CH3), 3.01 (s, 3H, CH3), 5.49 (m, 1H, CH),
7.09 (s, 1H, C8-H), 8.83 (s, 1H, C8-H); 13C NMR (CDCl3), 9.69 (CH3),
9.35 (CH3), 19.57 (CH3), 24.52 (CH3), 8.89 (CH3), 75.09 (O-CH), 116.73,
122.40, 123.83, 147.11, 154.00, 157.51, 160.15, 162.87, 163.90 (C-arom).
MS (EI): m/z (%) 287 (Mþ, 20), 231 (100), 202 (15). Anal. calcd for
C15H17N3OS: C, 62.69; H, 5.96; N, 14.62. Found: C, 62.73; H, 6.06; N, 14.39.
3-(2-Acetyloxyethyl)-7,9-dimethylpyrido[30,20:4,5]thieno[3,2-d]pyrimidin-
4-(3H)-one (6c): Mp 155–1588C (ethyl ether) (55% yield); IR: 1742 (COMe),

Analogues of Acyclonucleosides
2759
1
1667 (C55O), 1573 (C55N); H NMR (CDCl3): 1.91 (s, 3H, CH3CO), 2.49
(s, 3H, CH3), 2.73 (s, 3H, CH3), 4.19 (t, 2H, J ¼ 3.5 Hz, CH2), 4.28 (t, 2H,
J ¼ 3.5 Hz, CH2), 6.90 (s, 1H, C8-H), 7.96 (s, 1H, C2-H); 13C NMR
(CDCl3): 19.27, 20.68 (CH3), 24.50 (CH3), 45.86 (CH2), 61.56 (CH2),
122.13, 122.62, 124.35, 146.90, 147.31, 152.05, 157.33, (159.97), 162.83
(C-arom and CO), 170.39 (COMe). MS (EI): m/z (%) 317 (Mþ, 70), 231
(100), 274 (8), 275 (8), 175 (5), 87 (20). Anal. calcd. for C15H15N3O3S: C,
56.77; H, 4.76; N, 13.24. Found: C, 56.71; H, 4.54; N, 13.06.
4-(2-Acetyloxyethoxy)-7,9-dimethyl-pyrido[30,20:4,5]thieno[3,2-d]pyrimidine
(7c): Mp 107–1108C (diethyl ether) (24% yield); IR: 1745 (COMe), 1577
(C55N), 1130 (C-O-C); H NMR (CDCl3): 2.12 (s, 3H, CH3), 2.67 (s, 3H,
1
CH3), 2.68 (s, 3H, CH3), 4.54 (t, 2H, J ¼ 4.5 Hz, CH2) 4.82 (t, 2H,
J ¼ 4.5 Hz, CH2), 7.12 (s, 1H, C8-H), 8.81 (s, 1H, C2-H); 13C NMR
(CDCl3): 19.54 (CH3), 20.80 (CH3), 24.51 (CH3), 62.16 (CH2), 64.63,
(CH2), 116.25, 122.5, 123.54, 147.27, 153.73, 157.84, 160.45, 162.91,
163.44 (C-arom); 170.82 (COCH3). MS(EI): m/z (%) 317 (Mþ, 20), 231
(40), 87 (100). Anal. calcd. for C15H15N3O3S: C, 56.77; H, 4.76; N, 13.24.
Found: C, 57.11; H, 4.76; N, 13.04.
General Procedure for the Deprotection of Compounds 6c and 7c
A mixture of 6c and/or 7c (0.4 g, 1 mmol), methanol (10 ml), and concen-
trated aqueous ammonia (25%, 10 ml) was stirred at room temperature for
24 h. The solvent was removed by evaporation under reduced pressure; the
solid product was collected and recrystallized from methanol to give the
compounds 8 and 9 as pure product in 85 and 75% yield, respectively.
Data
3-(2-Hydroxyethyl)-7,9-dimethylpyrido[30,20:4,5]thieno[3,2-d]pyrimidin-
4(3H)-one(8): Mp 223–2258C (85% yield); IR: 3472 (OH), 1655 (C55O),
1566 (C55N); H NMR (DMSO): 2.60 (s, 3H, CH3), 2.88 (s, 3H, CH3),
1
3.73 (q, 2H, J ¼ 5.4 Hz, CH2), 4.15 (t, 2H, J ¼ 5.4 Hz, CH2), 5.01 (t, 1H,
J ¼ 5.4 Hz, OH), 7.29 (s, 1H, C8-H), 8.51 (s, 1H, C2-H); 13C NMR
(DMSO): 18.69 (CH3), 23.90 (CH3), 48.66 (CH2), 58.04 (CH2), 120.34,
122.60, 123.82, 146.33, 150.01, 151.66, 156.73, 159.60, 161.37 (C-arom
and CO). MS (EI): m/z (%) 275 (Mþ, 30), 231 (100), 214 (25), 202 (30),
131 (25), 43 (40). Anal. calcd. for C13H13N3O2S: C, 56.71; H, 4.76; N,
15.26. Found: C, 56.68; H, 4.64; N, 15.12.
7,9-Dimethyl-4-(2-hydroxyethyloxy)-pyrido[30,20:4,5]thieno[3,2-d]pyri-
midine (9): Mp 180–1838C (diethyl ether) (75% yield); IR: 3270 (OH),
1569 (C55N); H NMR (DMSO): 2.90 (s, 3H, CH3), 2.60 (s, 3H, CH3),
1

2760
A. F. Khattab, M. A. Zahran, and A. Saif
3.84 (q, 2H, J ¼ 5.0 Hz, CH2), 4.60 (t, 2H, J ¼ 4.8 Hz, CH2), 5.03 (t, 1H,
J ¼ 5.4 Hz, OH), 7.28 (s, 1H, C8-H), 8.85 (s, 1H, C2-H), 13C NMR
(DMSO): 18.51 (CH3), 23.52 (CH3), 58.50 (CH2), 68.30 (CH2), 14.40,
122.26, 122.15, 146.23, 153.78, 156.52, 160.00, 161.11, 162.96 (C-arom).
MS (EI): m/z (%) 275 (Mþ, 5), 231 (20), 202 (3), 31 (100). Anal. calcd. for
C13H13N3O2S: C, 56.71; H, 4.76; N, 15.26. Found: C, 56.83; H, 4.78; N, 15.00.
7,9-Dimethyl-3-(20-p-tolysulfolonyl)-pyrido[30,20:4,5]thieno[3,2-d]pyrimidin-
4(3H)-one (10): p-Toluenesulfonyl chloride (0.76 g, 4 mmol) was added to an
ice-cooled stirred solution of 9 (1.1 g, 4 mmol) in anhydrous pyridine (20 ml)
and left to stand overnight at 48C, then 4 h at room temperature. The pyridine
was removed by evaporation under reduced pressure, and the resulting gum
was triturated with ice water. The product solidified as a white precipitate
and was collected by filtration, dried, and recrystallized from ethanol to
give compound 10 as a colorless crystals. Mp 194–1968C (76% yield); IR:
1
1671 (CO), 1563 (C55N), 1173 (C-O-S), H NMR (CDCl3): 2.01 (s, 3H,
CH3), 2.69 (s, 3H, CH3), 2.93 (s, 3H, CH3), 4.29 (t, 2H, J ¼ 4.7 Hz, CH2),
4.44 (t, 2H, J ¼ 4.7 Hz, CH2), 7.00 (d, 2H, J ¼ 8.4 Hz, Ar-H), 7.13 (s, 1H,
C8-H), 7.58 (d, 2H, J ¼ 8.4 Hz, Ar-H), 8.06 (s, 1H, C2-H); 13C NMR
(CDCl3): 19.35 (CH3), 21.20 (CH3), 24.56 (CH3), 46.35 (CH2), 66.61
(CH2), 121.81, 122.77, 124.33, 127.50, 129.59, 145.11, 147.09, 147.39,
152.17, 156.94, 160.24, 162.84 (C-arom and CO). MS (EI): m/z (%) 429
(Mþ, 60), 274 (60), 231 (30), 91 (100). Anal. calcd. for C20H19N3O4S2: C,
55.93, H, 4.46; N, 9.78. Found: C, 56.22; H, 4.47; N, 9.62.
3-(2-Azidoethyl)-7,9-dimethylpyrido[30,20:4,5]thieno[3,2-d]pyrimidin-4(3H)-
one (11): A mixture of compound 10 (0.86 g, 2 mmol) and sodium azide
(0.13 g, 2 mmol) in anhydrous N,N-dimethylformamide (10 ml) was heated
with stirring for 2 h at 808C. The solvent was removed by evaporation
under reduced pressure and the remaining syrup triturated with ice water. A
white precipitate was collected by filtration, washed with ice water, and
dried. The product was recrystallized from ethanol to give 11 as colorless
crystals. Mp 170–1728C (60% yield); IR: 2105 (N3), 1672 (CO), 1572
(C55N); 1H NMR (CDCl3): 2.67 (s, 3H, CH3), 2.91 (s, 3H, CH3), 3.83
(t, 2H, J ¼ 5.4 Hz, CH2), 4.21 (t, 2H, J ¼ 5.4 Hz, CH2), 7.08 (s, 1H,C8-H),
8.16 (s, 1H, C2-H); 13C NMR (CDCl3): 19.29 (CH3), 24.53 (CH3), 46.39
(CH2), 49.37 (CH2), 122.69, 124.37, 147.05, 147.33, 147.44, 152.27,
157.27, 157.38, 160.00, 162.89 (C-arom and CO). MS (EI): m/z (%) 300
(Mþ, 30), 245 (100), 214 (15), 41 (30). Anal. calcd for C13H12N6OS: C,
51.99; H, 4.03; N, 27.98. Found: Cr, 52.04; H, 4.12; N, 27.71.
ACKNOWLEDGMENTS
The authors thank DANIDA for the financial support to carry out this work at
Monoufiya University through the project Development of New Drugs against

Analogues of Acyclonucleosides
2761
Hepatitis and E. B. Pedersen for making the spectral measurements at the
Chemistry Institute, Syddansk University, Odence M, Denmark.
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