Synthesis of some new S-DABO and HEPT analogues with expected biological activity against HBV

Article abstract of DOI:10.1081/SCC-120003633

Ethyl4-(3,4-dimethoxyphenyl)-2-methyl-3-oxobutanoate (1) is synthesized in a high yield from 3,4-dimethoxybenzylcyanide and 2-bromopropionate. Condensation of (1) with thiourea in EtOH/NaOEt afforded the thiopyrimidine (2). Alkylation of (2) with halo com

Full text of DOI:10.1081/SCC-120003633

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SYNTHESIS OF SOME NEW S-DABO AND HEPT
ANALOGUES WITH EXPECTED BIOLOGICAL ACTIVITY
AGAINST HBV
Mohammed Taha Abdel Aal a
a Chemistry Department, Faculty of Science, El-Menofeia University, Shebin El-Koom, Egypt
Version of record first published: 17 Aug 2006.
To cite this article: Mohammed Taha Abdel Aal (2002): SYNTHESIS OF SOME NEW S-DABO AND HEPT ANALOGUES WITH
EXPECTED BIOLOGICAL ACTIVITY AGAINST HBV, Synthetic Communications: An International Journal for Rapid Communication
of Synthetic Organic Chemistry, 32:9, 1365-1377
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SYNTHETIC COMMUNICATIONS, 32(9), 1365–1377 (2002)
SYNTHESIS OF SOME NEW S-DABO AND
HEPT ANALOGUES WITH EXPECTED
BIOLOGICAL ACTIVITY AGAINST HBV
Mohammed Taha Abdel Aal
Chemistry Department, Faculty of Science,
El-Menofeia University, Shebin El-Koom, Egypt
ABSTRACT
Ethyl4-(3,4-dimethoxyphenyl)-2-methyl-3-oxobutanoate (1) is
synthesized in a high yield from 3,4-dimethoxybenzylcyanide
and 2-bromopropionate. Condensation of (1) with thiourea in
EtOH/NaOEt afforded the thiopyrimidine (2). Alkylation of
(2) with halo compounds gave new thio-analogues of DABO’s
(3–7), whereas desulfurization of (2) by chloroacetic acid
afforded the uracil (3). Reaction of (3) with chloromethyl
ethers yielded new analogues of HEPT (10a,b).
The virally coded enzyme, reverse transcriptase (RT), is an attractive
target in the search for new antiviral agents against human immuno-
deficiency virus type-1 (HIV-1). This enzyme is a pivot in the retro viral
cycle of HIV as it with viral RNA as template synthesizes viral DNA for
integration in the host genome.1 Several specific inhibitors of HIV-1 RT
have been reported.2,3 Some of these are 1-[(2-hydroxyethoxy)methyl]-6-
(phenylthio)thymine (HEPT) derivatives and 3,4-dihydro-2-alkoxy-6-
benzyl-4-oxopyrimidines (DABO) derivatives. Since HEPT4 was recognized
as a non-nucleoside inhibitor of HIV-1, there has been a wide interest for
1365
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

1366
ABDEL AAL
development within this group of compounds that specifically inhibit the
HIV-1 enzyme reverse transcriptase (RT) of HIV type 1. Many reviews5-8
have been made about NNRTIs but the focus has mainly been on the
development and pharmacological aspects.
S-DABOs derivatives which are 2-alkylthio analogues of dihydro-
alkoxypyrimidines (DABO) and their activity against HIV-1 were also
reported.9 The 3-oxo ester (1) was prepared according to the method of
Pedersen et al.,10 by reaction of 3,4-dimethoxybenzylcyanide with ethyl-
2-bromopropionate in the presence of activated zinc in refluxing THF
for 8 h. The so formed 3-oxo ester (1) was converted into the 2-thiouracil
(2) by its reaction with thiourea and sodium in boiling ethanol for 20 h.
(Scheme 1).
Scheme 1.
The promising biological activity of various thio analogues of dihydro-
alkoxybenzyloxopyrimidines (DABOs) prompted us to synthesize the new
derivatives (3–7) to investigate their biological activities against HBV. The
reaction of (2) with different types of halo compounds as alkyl halides, halo

S-DABO AND HEPT ANALOGUES
1367
esters, and halo alkyl sulfides in a mixture of DMF/K2CO3 or
NaOMe/MeOH by stirring at room temperature for 18–24 h afforded the
desired
ones (3–7) in a fair yield (Scheme 2).
2-(alkylthio)-6-(30,40-dimethoxyphenylmethyl)-pyrimidine-4(1H)
Scheme 2.
Mai et al.11 have reported that alkylation of 6-(20,60-difluro-
phenylmethyl)-3,4-dihydro-5-methyl-2-thiopyrimidine-4(3H)-one with iodo-
methane in DMF at room temperature in the molar ratio 1 : 2 gave the
corresponding S-alkylated product. In our hands, treatment of (2) with
iodomethane in DMF and K2CO3 in molar ratio 1 : 1 or in excess afforded

1368
ABDEL AAL
the bis N-and S-alkylated product (3) as the sole product. However, the
reaction of (2) with iodoethane 1 : 1 in DMF and K2CO3 at room tempera-
ture gave only the mono S-alkylated product (4).
It is worthy to mention that the reaction of (2) with ethylbromo-
acetate in refluxing ethanol for 18 h afforded unexpectedly the correspond-
ing oxo analogue (9) as the sole product (TLC) through hydrolysis
process, while the reaction of (2) with the bromoester in DMF/K2CO3
at room temperature for 24 h gave the normal 2-alkylthio derivative (8)
(Scheme 3).
Scheme 3.
The synthesis of HET analogues could also be achieved by the desul-
furization of (2) using 10% aqueous chloroacetic acid at the refluxing tem-
perature for 20 h in 65% yield. The pyrimidine (9) was silylated by its
treatment with N,O-bis(trimethylsilyl)acetamide (BSA) in anhydrous
chloroform for 3h at room temperature under N 2. The silylated product
was treated with chloromethyl methyl ether and/or chloromethyl ethyl ether
to afford the corresponding uracil derivatives (10a,b), respectively
(Scheme 4). The elucidation of the structures of all new compounds was
confirmed by IR, 1H NMR, 13C NMR and MS. The compounds were
purified by chromatography on silica gel column. The IR spectra display
absorption bands in the regions 3436–3423 and 1689–1627 cmÀ1 corre-
sponded to NH and C¼O, respectively.

S-DABO AND HEPT ANALOGUES
1369
Scheme 4.
1
The H NMR spectra of the products exhibited the CH3 signals as a
singlet (3H) in the range 1.90–2.20 ppm, OCH3 signals as a singlet (3H) at
3.70–3.87 ppm, while the NH appeared as a singlet (1H) in the range 8.67–
12.34 ppm. In the 13C NMR spectra, the CH3 signals appeared in the range
9.72–14.96 ppm, the OCH3 carbons at 55.19–56.88 and the C¼O at 158.10–
163.32 ppm.
Viral screening against HBV was tested at the National Liver Institute,
El-Menofeia University, Egypt.
Maintenance media were added to the cell culture (Hep G2 2.2.15)
together with the tested compounds (final concentration ¼ 10 mM). The
supernatant liquid was collected after one, two and/or three weeks. The
DNA replication was estimated by the PCR (polymerase chain reaction) tech-
nique. The percentage inhibition could be calculated by the relation between
the blanc experiment (containing maintenance media without the tested
compounds) and the results obtained after the above mentioned periods.
The percentage cytotoxicity could be estimated by the relation between
the number of the living and dead cells after three weeks counted by the
Haemocytometer. Compounds 3, 4, 5, 8 and 10a, b showed high viral
replication inhibition and low cytotoxicity. Compounds 6 and 7 showed
moderate inhibition with moderate cytotoxicity.

1370
ABDEL AAL
EXPERIMENTAL
All melting points are uncorrected. IR spectra (KBr) were obtained
using Perkin Elmer 1720 Infrared Fourier Transform Spectrometer. NMR
spectra were recorded on a Varian Gemini 2000 NMR spectrometer at
300 MHz for 1H and 75 MHz for 13C or on a Brucker AC-250 FT spectrom-
1
eter at 250 MHz for H and at 62.9 MHz 13C with TMS as an internal
standard. EI mass spectra were recorded on a Finnigan Mat SSQ 710.
The progress of the reaction was monitored by TLC analytical silica gel
plates 60 F254. Merk silica gel (0.040–0.063) was used for column chroma-
tography. Tetrahydrofuran (THF) was distilled from sodium/bezophenone
prior to use. All the newly prepared compounds gave satisfactory C, H, N.
Synthesis of Ethyl-2-methyl-4-(3,4-dimethoxyphenyl)-
3-oxobutyrate (1)
Activated zinc dust (zinc dust washed sequentially with 3M aq. HCl,
distilled H2O, EtOH, Et2O, and then dried in vacuo); (38 g, 580 mmol) was
suspended in refluxing THF (280 ml) under nitrogen. A few drops of ethyl 2-
bromopropionate were added to initiate the reaction. When the mixture
turned green (approx. 3h), 3,4-dimethoxybenzylcyanide (14 g, 79 mmol)
was added in one portion, followed by slow addition (6 h) of ethyl-2-
bromopropionate (36.7 g, 203 mmol). The mixture was refluxed for 30 min.
After cooling and dilution with 700 ml THF, the reaction mixture was stir-
red with 130 ml 50% K2CO3 for 6 h. The THF fraction was decanted and
the water fraction was washed with THF (3 Â 100 ml). The combined THF
fractions were stirred with 10% aq. HCl (120 ml) at room temperature for
45 min. The solvent was evaporated and the residue was redissolved in
400 ml CH2Cl2, washed with sat. NaHCO3, dried over anhydrous Na2SO4
and evaporated under reduced pressure to furnish after column chromato-
graphy on silica gel using ether/ligoin (1 : 1 v/v) the oxo-ester (1) as colorless
oil, yield 92.7%.
IR (KBr): 1718 (C¼O) cmÀ1
.
1H NMR (DMSO-d6/TMS): d ¼ 1.48 (d, 3H, CH3), 1.16 (t, 3H, CH3,
j ¼ 7.08), 3.67 (s, 2H, CH2), 3.7 (s, 6H, 2 Â OCH3), 4.07 (q, 2H, CH2-CH3,
j ¼ 6.96), 4.09 (m, 1H, CH), 6.66–6.88 (aromatic H).
13C NMR (DMSO-d6/TMS): d ¼ 12.55 (CH3), 13.76 (CH3-CH2), 47.24
(CH2-ph), 51.12 (CH), 55.35 (OCH3), 55.42 (OCH3), 60.73( CH2-O), 111.83,
113.55, 121.87, 126.46, 147.87, 148.69 (aromatic carbons), 170.30 (C¼O),
204.23( C¼O).
C15H20O5 (280.32), Calc.: C 64.37, H 7.19. Found: C 63.97, H 7.20.

S-DABO AND HEPT ANALOGUES
Reaction of Ethyl-2-methyl-4-(3,4-dimethoxyphenyl)-
1371
3-oxobutyrate (1) with Thiourea Formation of 5-Methyl-6-
(3,4-dimethoxybenzyl)-2-thio-4-1(H) Pyrimidine (2)
Compound 1 (1.68 g, 5.99 mmol) was added to a mixture of sodium
(3.0 g, 130 mmol) and thiourea (6.95 g, 91.3 mmol) in abs. ethanol (70 ml).
The mixture was refluxed for 18 h (TLC). After cooling, the solvent was
removed in vacuo and the residue was dissolved in water (50 ml) and neu-
tralized with HCl (25 ml). The precipitate was collected, washed with water
and recrystallized from EtOH to give (2) as white crystals, yield 9.3g
53.14%; m.p. 191–192ꢀC.
IR (KBr): 3436 (NH), 3154 (NH), 1684 (C¼O) cmÀ1
.
1H NMR (DMSO-d6/TMS): d ¼ 1.83(s, 3H, CH 3), 3.69 (s, 2H, CH2,),
3.74 (s, 6H, 2 Â OCH3), 6.75 (d, 1H, aromatic), 6.89 (d, 2H, aromatic), 12.34
(sbr., 2H, 2 Â NH).
13C NMR (DMSO-d6/TMS): d ¼ 9.87 (H3C-C¼), 34.40 (CH2), 55.44
(2 Â OCH3), 110.91 (C-5), 111.99, 112.44, 119.98, 128.54 (aromatic carbons),
149.91 (C-6), 161.91 (C-4), 173.95 (C-2).
C14H16N2O3S(292.35), Calc.: C 57.52, H 5.52, N 9.58. Found: C 57.48,
H 5.20, N 9.43.
General Procedure for the Preparation of Compounds 3–7
A mixture of (2) (292 mg, 1 mmol), the appropriate halo compounds
(1 mmol) and anhydrous potassium carbonate (138 mg, 1 mmol) in an-
hydrous N,N-dimethyformamide (3ml) or NaOMe/MeOH (1.1 mmol) was
stirred overnight at room temperature. After treatment with water (60 ml),
the solution was extracted with ethylacetate (3 Â 50 ml). The organic layers
were collected, washed with brine (3 Â 50 ml), dried over anhydrous Na2SO4
and evaporated till dryness under vacuo to furnish the corresponding crude
2-alkylthio derivatives (3–7).
6-(30,40-Dimethoxyphenylmethyl)-3,5-dimethyl-2-(methylthio)pyrimidin-
4(3H)-one (3): Yield (0.24 g, 47.0%), m.p. 89–90ꢀC, purified on silica gel
column using ethyl acetate/ligroin 1 : 1 (v/v).
IR (KBr): 1656 (C¼O) cmÀ1
.
1H NMR (CDCl3): d ¼ 1.58 (s, 3H, CH3), 2.13(s, 3H, S-CH 3), 2.52 (s,
2H, CH2), 3.49 (s, 3H, N-CH3), 3.857 (s, 3H, OCH3), 3.86 (s, 3H, OCH3),
6.79 (d, 1H, H-50), 6.85 (s, 1H, H-60), 7.27 (s, 1H, H-20).
13C NMR (CDCl3/TMS): d ¼ 11.52 (CH3-C¼), 14.80 (S-CH3), 30.48
(CH2), 40.46 (N-CH3), 55.19 (OCH3), 55.43(O CH3), 111.76 (C-20), 112.81
(C-5), 113.54 (C-50), 120.60 (C-60), 130.43 (C-10), 158.63( C¼O), 162.09 (C-2).

1372
ABDEL AAL
Mass spectrum (m/z) ¼ 320 (Mþ, 100), 305 (Mþ-CH3, 31), 291
(Mþ-NCH3, 2.5), 290 (Mþ-3CH , 12.5), 182 (Mþ-3,4-dimethoxyphenyl,
3
12.5), 152 (þCH2–3,4-dimethoxyphenyl, 4), 138 (3,4-dimethoxyphenylþ,
23.8), 91 (þCH2Ph, 4).
C16H20N2O3S (320.40), Calc.: C 59.98, H 6.29, N 8.74, S 9.99. Found:
C 60.07, H 6.22, N 8.77, S 10.03.
6-(30,40-Dimethoxyphenylmethyl)-3,4-dihydro-5-methyl-2-(ethylthio)pyri-
midin-4(3H)-one (4): Yield (56%), m.p. 161–162ꢀC.
IR (KBr): 3434 (NH), 1656 (C¼O) cmÀ1
.
1H NMR (CDCl3/TMS): d ¼ 1.34 (t, 3H, CH3-CH2), 2.13(s, H3 ,
CH3), 3.14 (q, 2H, CH2-CH3), 3.87 (s, 6H, 2 OCH3), 6.80 (d, 1H, H-50),
6.84 (s, 1H, H-60), 7.30 (s, 1H, H-20).
13C NMR (CDCl3/TMS): d ¼ 11.09 (CH3-CH2), 14.96 (CH3-C¼),
25.48 (CH2), 41.07 (CH2-S), 56.29 (OCH3), 56.34 (OCH3), 111.58 (C-5),
112.72 (C-20), 116.39 (C-50), 121.34 (C-60), 130.95 (C-10), 148.11 (C-30),
149.24 (C-40), 156.85 (C-2), 162.87 (C¼O), 165.93(C-2).
Mass spectrum (m/z) ¼ 320 (Mþ, 100), 305 (Mþ-CH3, 52.8), 291 (Mþ-
C2H5, 17.5), 287 (Mþ-SH, 28.4), 259 (Mþ-SEt, 6.5), 182 (Mþ-3,4-
dimethoxyphenyl, 2.2), 152 (þCH2-3,4-dimethoxyphenyl, 3.7), 138 (3,4-
dimethoxyphenylþ, 22.5), 91 (þCH2Ph, 13.4).
C16H20N2O3S (320.40), Calc.: C 59.98, H 6.29, N 8.74. Found: C
60.03, H 6.34, N 9.01.
6-(30,40-Dimethoxyphenylmethyl)-3,4-dihydro-5-methyl-2-(cyclopentyl-
thio)pyrimidin-4(3H)-one (5): Yield (58%); m.p. 145–146ꢀC.
IR (KBr): 3436 (NH), 1651 (C¼O) cmÀ1
.
1H NMR (DMSO-d6/TMS): d ¼ 1.54 (m, 4H, 2 Â 2 CH2), 1.96 (s, 3H,
CH3), 2.05 (m, 4H, 2 Â CH2), 3.33 (s, 2H, CH2), 3.705 (s, 3H, OCH3), 3.714
(s, 3H, OCH3), 3.76 (m, 1H, H-S), 6.76 (d, 1H, H-50), 6.84 (s, 1H, H-60); 6.87
(s, 1H, H-20), 12.47 (bs, 1H, NH).
13C NMR (DMSO-d6/TMS): d ¼ 10.28 (CH3), 24.22 (Cg-Cd), 32.61
(Cb-Cꢀ), 42.93( Ca), 55.29 (OCH3), 55.34 (OCH3), 111.74 (C-20), 112.87
(C-5), 114.60 (C-50), 120.71 (C-60), 130.57 (C-10), 147.28 (C-40), 148.44
(C-30), 154.80 (C-6), 158.10 (C¼O), 162.10 (C-2).
Mass spectrum (m/z) ¼ 360 (Mþ, 84.5), 345 (Mþ-CH3, 4.5), 329 (Mþ-
OCH3, 7.3), 327 (Mþ-SH, 100), 291 (Mþ-cyclopentyl, 35.7), 259 (Mþ-S-
cyclopentyl, 101), 152 (þCH2-3,4-dimethoxyphenyl, 12.2), 138 (3,4-
dimethoxyphenylþ, 31.3), 101 (Sþ-cyclopentyl, 3.7), 91 (þCH2Ph, 10.2).
C19H24N2O3S (360.37), Calc.: C 63.33, H 6.71, N 7.77. Found: C
62.92, H 6.53, N 7.72.
6-(30,40-Dimethoxyphenylmethyl)-3,4-dihydro-5-methyl-2-(allylthio)pyr-
imidin-4(3H)-one (6): Yield (51%), m.p. 155–156ꢀC.
IR (KBr): 3435 (NH), 1659 (C¼O) cmÀ1
.

S-DABO AND HEPT ANALOGUES
1373
1H NMR (DMSO-d6/TMS): d ¼ 1.96 (s, 3H, CH3), 3.34 (s, 2H, CH2),
3.62 (d, 2H, CH2-CH¼), 3.74 (s, 3H, OCH3), 3.78 (s, 3H, OCH3), 5.14 (dd,
2H, CH2), 5.85 (m, 1H, CH¼CH2), 6.75 (d, 1H, H-50), 6.84 (s, 1H, H-60),
6.88 (s, 1H, H-20).
13C NMR (DMSO-d6/TMS): d ¼ 10.33 (CH3), 32.12 (CH2), 39.59
(S-CH2), 55.29 (OCH3), 55.44 (OCH3), 111.81 (C-20), 112.79 (C-5), 117.96
(CH2¼CH), 120.59 (C-60), 126.50 (CH¼CH2), 133.49 (C-10), 147.30 (C-40),
148.47 (C-30), 157.50 (C-6), 158.50 (C¼O), 167.32 (C-2).
Mass spectrum (m/z) ¼ 332 (Mþ, 100), 317 (Mþ-CH3, 5.11), 299 (Mþ-
SH, 38.60), 291 (Mþ-CH2¼CH-CH2, 12.87), 259 (Mþ-S-CH2-CH¼CH2,
3.50), 152 (þCH2-3,4-dimethoxyphenyl, 3.51), 138 (3,4-dimethoxyphenylþ,
12.87), 91 (þCH2Ph 5.85).
C17H20N2O3S (332.42), Calc.: C 61.42, H 6.06, N 8.43. Found: C
61.29, H 6.18, N 8.39.
6-(30,40-Dimethoxyphenylmethyl)-5-methyl-2-[(methylthiomethyl)thio]
pyrimidin-4(3H)-one (7): Yield (53%), m.p. 153–155ꢀC; crystallized from
ethylacetate/legroin 1 : 1 (v/v).
IR (KBr): 3435 (NH), 1659 (C¼O) cmÀ1
.
1H NMR (CDCl3): d ¼ 2.11 (s, 3H, CH3), 2.17 (s, 3H, S-CH3), 3.78 (s,
2H, CH2), 3.85 (s, 3H, OCH3), 3.86 (s, 3H, OCH3), 4.31 (s, 2H, S-CH2),
12.55 (s, 1H, NH).
13C NMR (CDCl3): d ¼ 10.70 (CH3-C¼), 15.55 (S-CH3), 3.67 (CH2),
40.62 (S-CH2), 55.91 (OCH3), 111.91 (C-20), 112.31 (C-5), 116.61 (C-50),
120.97 (C-60), 130.27 (C-10), 147.75 (C-40), 148.90 (C-3), 155.30 (C-6),
162.31 (C¼O), 165.32 (C-2).
Mass spectrum (m/z) ¼ 352 (20.0), 305 (Mþ-S-CH3, 100), 291 (Mþ-
CH2-S-CH3, 6.3), 259 (Mþ-SCH2S-CH3, 7.00), 152 (þCH2-3,4-dimethoxy-
phenyl, 2.5), 138 (3,4-dimethoxyphenylþ, 6.3), 91 (þCH2Ph 3.7).
C16H20N2O3S (352.45), Calc.: C 54.53, H 5.72, S 18.19. Found: C
54.38, H 5.71, S 18.03.
Reaction of (2) with Ethylbromoacetate: Formation of
6-(30,40-Dimethoxyphenylmethyl)-5-methyl-2-
[(carboethoxymethyl)thio]pyrimidin-4(3H)-one (8)
To 0.29 g (1 mmol) of (2) in 2 ml anhydrous DMF, 0.138 g (1 mmol) of
K2CO3 and 0.11 ml (1 mmol) of bromoester were added. The reaction
mixture was stirred at room temperature for 29 h. TLC (ethylacetate/ligroin
1 : 1 v/v) revealed disappearance of the starting material and appearance of
one spot. The reaction mixture was worked up by adding (50 ml) water and
extraction with ethylacetate. The aqueous phase was extracted three times

1374
ABDEL AAL
(3 Â 10 ml) with ethylacetate. The combined extractions were washed with
saturated NaCl (2 Â 50 ml), dried over MgSO4, filtered and concentrated in
vacuo to furnish the title compound (8). Yield (59%), m.p. 170–171ꢀC.
IR (KBr): 3435 (NH), 1659 (C¼O) cmÀ1
.
1H NMR (CDCl3): d ¼ 1.22 (t, 3H, CH3-CH2), 2.09 (s, 3H, CH3-C¼),
3.84 (s, 2H, CH2), 3.87 (s, 2H, SCH2), 3.88 (s, 6H, OCH3), 4.13(q, 2H,
CH2), 6.77 (d, 1H, H-50), 6.8 (s, 1H, H-60), 7.26 (s, 1H, H-20), 12.48 (sb,
1H, NH).
13C NMR (CDCl3): d ¼ 10.55 (CH3-CH2), 13.99 (CH3-C¼), 15.55
(S-CH3), 32.78 (CH2), 40.49 (CH2-C¼O), 55.85 (2 Â OCH3), 61.85
(OCH2), 111.23( C-20), 112.24 (C-5), 116.72 (C-50), 120.84 (C-60), 130.35
(C-10), 147.85 (C-40), 149.03( C-30), 154.97 (C-6), 162.32 (C¼O), 165.33
(C-2), 168.52 (O-C¼O).
Mass spectrum (m/z) ¼ 378 (Mþ, 100), 363 (Mþ-CH3, 5.0), 347 (Mþ-
OCH3, 2.0), 333 (m -OEt, 21.3, 305 (Mþ -COOEt, 66.2), 291 (Mþ-CH2-
COOEt, 32.5), 259 (Mþ -SCH2COOEt, 6.5), 152 (þCH2-3,4-dimethoxy-
phenyl, 3.1), 138 (3,4-dimethoxyphenylþ, 24.5), 119 (þSCH2COOEt, 3.5)
91 (þCH2Ph 5.0).
C18H22N2O5S (378.44), Calc.: C 57.13, H 5.85, N 7.40. Found: C 56.
93, H 5.79, N 7.38.
Reaction of (2) with Ethylbromoacetate: Formation of
6-(30,40-Dimethoxyphenylmethyl)-5-methyluracil (9)
A mixture of (2) (292 mg, 1 mmol) and ethylbromoacetate (167 g,
1 mmol) was refluxed in enthanol (10 ml) for 18 h (TLC). The solvent was
evaporated till dryness under vacuo and the residual solid was crystallized
from methanol to afford (9) as a colorless crystal. Yield (55%); m.p.
220–222ꢀC.
Reaction of (2) with Chloracetic Acid: Formation of
6-(30,40-Dimethoxyphenylmethyl)-5-methyluracil (9)
A mixture of (2) (6 g, 20 mmol) and 600 ml (10%) aqueous chloroacetic
acid was refluxed for 20 h (TLC). The mixture was cooled to room tempera-
ture. The precipitated solid was filtered off and washed with ethanol (15 ml)
followed by ether (15 ml) to give (9) as a colorless crystals, yield (3.8 g,
67.0%); m.p. 220–222ꢀC.
IR (KBr): 3432 (NH), 3167 (NH), 1707 (C¼O), 1664 (C¼O) cmÀ1
.

S-DABO AND HEPT ANALOGUES
1375
1H NMR (DMSO-d6/TMS): d ¼ 1.80 (s, 3H, CH3), 3.66 (s, 2H, CH2),
3.72 (s, 3H, OCH3), 3.75 (s, 3H, OCH3), 6.79–6.93(aromatic H), 10.75
(s, 1H, NH), 11.01 (s, 1H, NH).
13C NMR (DMSO-d6/TMS): d ¼ 9.72 (CH3-C¼), 34.94 (CH2), 55.44
(2 Â OCH3), 104.75 (C-5), 111.98, 112.43, 120.04, 128.76 (aromatic carbons),
147.62 (C-6).
C14H16N2O4 (276.29), Calc.: C 60.86, H 5.84. Found: C 60.81, H 5.83.
Reaction of (9) with Chloromethyl Methyl Ether and/or
Chloromethyl Ethyl Ether: Formation of
6-(30,40-Dimethoxyphenylmethyl)-1-methoxymethyl-
5-methyluracil (10a) and 6-(30,40-Dimethoxyphenylmethyl)-
1-ethoxymethyl-5-methyluracil (10b)
Compound (9) (0.276 g, 1 mmol) was suspended in anhydrous chloro-
form (20 ml), N,O-bistri-methylsilyl acetamide (0.60 g, 2.5 mmol) was added
while stirring under nitrogen atmosphere at room temperature for 2 h until
the solution became clear. The appropriate chloroether (0.15 mmol) was
added dropwise and stirring was continued for 8–10 h until the starting
material was consumed (TLC). Saturated sod. bicarbonate solution (7 ml)
and ethanol (20 ml) were added to the reaction mixture while stirring. The
organic layer was separated, washed with water and dried over anhydrous
sod. Sulphate to afford (10a) and/or (10b).
6-(30,40-Dimethoxyphenylmethyl)-1-methoxymethyl-5-methyluracil (10a):
Yield (55%); m.p. 110–111ꢀC, crystallized from ethylacetate/ligroin 1 : 1 (v/v).
IR (KBr): 3435 (NH), 1659 (C¼O) cmÀ1
.
1H NMR (CDCl3): d ¼ 2.20 (s, 3H, CH3), 3.50 (s, 3H, O-CH3), 3.80 (s,
6H, 2 Â OCH3), 4.28 (s, 2H, CH2), 5.10 (s, 2H, OCH2-N), 6.50–6.80 (m, 3H,
aryl-H), 9.8 (s, 1H, NH).
13C NMR (CDCl3): d ¼ 10.75 (CH3-C¼), 33.35 (CH2), 55.86
(2 Â OCH3), 56.88 (OCH3), 74.10 (OCH2-N), 110.72 (C-5), 111.75 (C-20),
114.16 (C-50), 119.1 (C-60), 126.95 (C-10), 147.50 (C-40), 147.80 (C-30), 149.67
(C-6), 152.11 (C¼O), 164.21 (C-2).
Mass spectrum (m/z) ¼ 320 (Mþ, 31.9), 289 (Mþ-OCH3, 11.1), 288
(Mþ-O2, 29.6), 275 (Mþ-CH2O-CH3, 3.7), 138 (3,4-dimethoxyphenylþ,
5.18), 91 (þCH2Ph, 6.66).
C16H20N2O5 (320.34), Calc.: C 59.99, H 6.29, N 8.74. Found: C 60.11,
H 5.95, N 8.62.
6-(30,40-Dimethoxyphenylmethyl)-1-ethoxymethyl-5-methyluracil (10b):
Yield (43%); m.p. 130–131ꢀC, crystallized from ethylacetate/ligroin 1 : 1 (v/v).
IR (KBr): 3423 (NH), 1689 (C¼O), 1627 (C¼O) cmÀ1
.

1376
ABDEL AAL
1H NMR (CDCl3): d ¼ 1.20 (t, 3H, CH3), 2.03(s, 3H, CH 3-C¼), 3.62
(q, 2H, CH2-CH3), 3.85 (3, 3H, OCH3), 3.860(s, 3H, OCH3), 4.10 (s, 2H,
CH2), 5.16 (s, 2H, OCH2-N), 6.63(d, 1H, H-5 ), 6.79 (s, 1H, H-20), 6.80 (d,
1H, H-60), 8.67 (s, 1H, NH).
13C NMR (CDCl3): d ¼ 10.96 (CH3-CH2), 15.07 (CH3-C¼), 33.52
(CH2-CH3), 55.95 (2 Â OCH3), 56.95 (CH2), 72.076 (OCH2), 74.10
(OCH2-N), 110.72 (C-5), 111.75 (C-20), 114.16 (C-50), 119.2 (C-60), 148.38
(C-10), 149.62 (C-40), 149.92 (C-30), 155.50 (C-6), 159.21 (C¼O), 163.66 (C-2).
Mass Spectrum (m/z) ¼ 334 (Mþ, 25.9), 303 (Mþ-OCH3, 3.7), 288
(Mþ-EtOH, 45.88), 275 (Mþ-CH2O-C2H5, 4.4), 186 (þCH2-3,4-dimethoxy-
phenyl, 7.4), 138 (3,4-dimethoxyphenylþ, 14.1), 107 (þPhOMe, 8.14), 91
(þCH2Ph, 2.96), 77. (þPh, 8.14), 59 (CH3CH2OCH2þ, 21.46).
C17H22N2O5 (334.37), Calc.: N 8.38. Found: N 7.94.
ACKNOWLEDGMENT
I’m really indebted to Prof. Dr. E. B. Pedersen for much kind advice
and fruitful discussions as well as for giving me the chance to carry out this
research work at his laboratory in Chemistry Department, Odense
University, Denmark.
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Received in the USA May 10, 2001