Synthesis of 1-(alkyl)-5-dimethylamino-6-phenethyluracils as potent nonnucleoside HIV-1 RT inhibitors

Article abstract of DOI:10.1080/00397910701412737

1-(Alkyl)-5-dimethylamino-6-phenethyl uracils (1) and (2) are analogs of MKC-442, which is a very potent inhibitor of HIV-1 reverse transcriptase. The target compound 1 was synthesized by the first approach, from the corresponding 1,3-dibenzyl-5-(dimethylamino)-6-phenethylpyrimidine-2,4(1H,3H)-dione (7), which was synthesized in four steps from 6-methyluracil (3) by nitration, benzylation, reduction, and methylation of the amino group. Compound 7 was then debenzylated to give the complete deprotected compound 8 with very low yield. To improve the yield, another pathway was developed for introducing the ethoxymethyl group at N-1 of the uracil ring first. The result of adjusting reaction sequences increased the overall yield dramatically. All synthesized compounds were tested for their inhibition of HIV-1 reverse transcriptase, and moderate activity was found for target compound 1. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701412737

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Synthesis of
1‐(Alkyl)‐5‐dimethylamino‐6‐phenethyluracils
as Potent Nonnucleoside HIV‐1 RT Inhibitors
Xiaowei Wang a , Yanli Chen a , Ying Guo b , Amin Li a , Xiaoyan Ma b & Junyi
Liu a b
a Department of Chemical Biology, School of Pharmaceutical Science, Peking
University, Beijing, China
b State Key Laboratory of Nature and Biomimetic Drugs, Peking University,
Beijing, China
Version of record first published: 11 Jul 2007
To cite this article: Xiaowei Wang, Yanli Chen, Ying Guo, Amin Li, Xiaoyan Ma & Junyi Liu (2007): Synthesis
of 1‐(Alkyl)‐5‐dimethylamino‐6‐phenethyluracils as Potent Nonnucleoside HIV‐1 RT Inhibitors, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:14,
2421-2431
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Synthetic Communicationsw, 37: 2421–2431, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701412737
Synthesis of 1-(Alkyl)-5-dimethylamino-6-
phenethyluracils as Potent Nonnucleoside
HIV-1 RT Inhibitors
Xiaowei Wang and Yanli Chen
Department of Chemical Biology, School of Pharmaceutical Science,
Peking University, Beijing, China
Ying Guo
State Key Laboratory of Nature and Biomimetic Drugs, Peking
University, Beijing, China
Amin Li
Department of Chemical Biology, School of Pharmaceutical Science,
Peking University, Beijing, China
Xiaoyan Ma
State Key Laboratory of Nature and Biomimetic Drugs, Peking
University, Beijing, China
Junyi Liu
Department of Chemical Biology, School of Pharmaceutical Science,
Peking University, Beijing, China and State Key Laboratory of Nature
and Biomimetic Drugs, Peking University, Beijing, China
Abstract: 1-(Alkyl)-5-dimethylamino-6-phenethyl uracils (1) and (2) are analogs of
MKC-442, which is a very potent inhibitor of HIV-1 reverse transcriptase. The target
compound 1 was synthesized by the first approach, from the corresponding 1,3-
dibenzyl-5-(dimethylamino)-6-phenethylpyrimidine-2,4(1H,3H)-dione (7), which was
synthesized in four steps from 6-methyluracil (3) by nitration, benzylation, reduction,
Received December 14, 2006
Address correspondence to Xiaowei Wang, Department of Chemical Biology,
School of Pharmaceutical Science, Peking University, Beijing 100083, China.
E-mail: xiaowei0301@china.com.cn
2421

2422
X. Wang et al.
and methylation of the amino group. Compound 7 was then debenzylated to give the
complete deprotected compound 8 with very low yield. To improve the yield, another
pathway was developed for introducing the ethoxymethyl group at N-1 of the uracil
ring first. The result of adjusting reaction sequences increased the overall yield dramati-
cally. All synthesized compounds were tested for their inhibition of HIV-1 reverse tran-
scriptase, and moderate activity was found for target compound 1.
Keywords: 5-dimethylamino-6-phenethyluracils, HIV-1 reverse transcriptase, nonnu-
cleoside reverse transcriptase inhibitors
Reverse transcriptase (RT) performs several critical roles in the replicative
cycle of the human immunodeficiency virus (HIV), and thus considerable
effort has been directed toward this enzyme as a target for therapies in
treating Acquired Immunodeficiency Syndrome (AIDS). During the past six
years, nonnucleoside reverse transcriptase inhibitors (NNRTIs)[1] have
gained an increasing role in the therapy of HIV infections. The era of the
NNRTIs started with the discovery of 1-[(2-hydroxyethoxy)methyl]-6-(phe-
nylthio) thymine (HEPT)[2,3] (Fig. 1) as a specific HIV-1 inhibitor, which
snugly fit into a specific, allosteric pocket (near the catalytic site) of the
HIV-1 reverse transcriptase and thus disrupts its enzymatic activity. From
then on, there has been a growing interest in the family of HEPT, and a
large number of analogs of HEPT have been designed and synthesized. The
6-benzyl-1-(ethoxymethyl)-5-isopropyluracil (MKC-442)[4] belongs to this
class of compounds and serves as a lead in NNRTI research program.
Structure–activity relationship (SAR) studies of MKC-442 have shown
that isopropyl group in the 5-position of the pyrimidine ring causes a
parallel change in the conformation of the 6-benzyl group, which triggers a
conformational switching of the protein structure of RT.[5] Therefore, replace-
ment of the 5-methyl group in the base moiety with the bulkier dimethylamino
group may potentiate their anti-HIV activity. It was considered that an
additional hydrogen bond might form between the amino acid of the
mutated RT with the dimethylamino group, and then it would be binding
the inhibitor more strongly to the mutated enzyme.
Figure 1. Structures of HEPT, MKC-442, and compound 1.

1-(Alkyl)-5-dimethylamino-6-phenethyluracils
2423
At the same time, as part of our research program in this area, preparation
of the 6-phenylethyl analogs was carried out to investigate the optimum distance
between these two ring systems for activity. So far, to the best of our knowledge,
no information is available concerning the 5-dimethylamino and 6-phenethyl
groups used as examples of new analogs of MKC-442. Such compounds
looked like an attractive objective because they have a more flexible confor-
mation then the 5-isopropyl-6-benzyl group in MKC-442. On the other hand,
the modifications of MKC-442 derivatives at the 5- and 6-positions could aid
in the development of a subset of analogues of MKC-442, which could
increase the activity against HIV-1 RT with low cytotoxicity.
To synthesize the 1-(alkyl)-5-dimethyamino-6-phenethylpyrimidine-
2,4(1H,3H)-dione (1) and (2), a conventional pathway was chosen
(Scheme 1), in which the carbon anion of 6-methyl in 5-nitro-6-methyluracil
(4) would be a key active intermediate. Compound 4 was prepared in 81%
yield according to the modified method of Osten[6] by the nitration with
fuming HNO3-P2O5. The 6-methyl protons of compound 4 are more active
because of the 5-nitro group. Compound 4 was reacted with 3 molar equiva-
lents of NaH and 3 molar equivalents of benzyl bromide to give 1,3-dibenzyl-
5-nitro-6-phenethylpyrimidine-2,4 (1H,3H)-dione (5), which was then
reduced by sodium dithionite (Na2S2O4), according to the same conditions
Han,[6] to afford 5-amino-1,3-dibenzyl-6-phenethyl pyrimidine-2,4(1H,3H)-
dione (6) with higher yield.
The amino compound 6 was treated with iodomethane (CH3I) in CH3CN
in the presence of sodium hydride or reacted with CH3I in the presence of
potassium carbonate, leading to the desired dimethylamino product 7 in
Scheme 1.

2424
X. Wang et al.
30–40% yield respectively. Subsequently, the deprotection of benzyl group of
7 was unsuccessful with usual reagents such as TiCl4,[7] ceric ammonium
nitrate (CAN),[8] trifluoroacetic acid (TFA),[9] BBr3,[10] and Pd/C-H2 which
gave no or multiple products, according to thin-layer chromatography
[11]
(TLC). However, deprotection using 10%Pd/C-HCOONH4
in methanol
for 3 days provides 5-(dimethylamino)-6-phenethylpyrimidine-2,4(1H,3H)-
dione (8) in only 21% yield and the mono-benzylated 2 in 51% yield.
It is noteworthy that the deprotection at N-3 is preferable to that at N-1,
N-1 benzyl is more stable than that at the 3-position. In an attempt to obtain
a better yield of 8, the reaction was carried out in different solvents
(MeOH, EtOH, THF, and DMF) and various proportions of HCOONH4 at
reflux for 7 days, but without any success. To obtain the target molecular 1,
compound 8 was silylated in situ with N,O-bis-(trismethylsily) acetamide
(BSA) in CH3CN and then alkylated with chloromethyl ethyl ether[12] to
give the desired 5-(dimethylamino)-1-(ethoxymethyl)-6-phenethylpyrimi-
dine-2,4(1H,3H)-dione (1) in 50% yield after column chromatography. The
overall yield of 1 in six steps from 3 does not exceed 2%.
Because difficulties were encountered with the poor yield and deprotec-
tion of N1-benzyl group of 7, the possibility of a more efficient synthesis of
compound 1 was considered. As reported, the N-1 position of uracil is more
active than the N-3 position in the nucleophilic substituted reaction.
Therefore, we considered that if the introduction order of the N-1 ethoxy-
methyl group of the uracil ring could be changed, a possible approach to
1 could be devised as outlined in Scheme 2. First, treatment of 5-nitro-6-
methyluracil (4) with BSA and chloromethylethyl ether in CH3CN afforded
the 1-(ethoxymethyl)-6-methyl-5-nitropyrimidine-2,4(1H,3H)-dione (9), which
was followed by treament with 2.5 equivalents of benzyl bromide and NaH
in dry THF to give the benzylated product 3-benzyl-1-(ethoxymethyl)-5-
nitro-6-phenethylpyrimidine-2,4(1H,3H)-dione (10) in 85% yield.
Scheme 2.

1-(Alkyl)-5-dimethylamino-6-phenethyluracils
2425
Subsequently, conversion of 10 to 5-amino compound 11 was performed in
excellent yield by the reduction with sodium dithionite (Na2S2O4) in MeOH
according to the previously mentioned method.[6] Compound 11 was methyl-
ated using NaH and CH3I to give 3-benzyl-5-(dimethylamino)-1-(ethoxy-
methyl)-6-phenethylpyrimidine-2,4(1H,3H)dione (12) in 87% yield. The
deprotection of the N-3 benzyl group was realized by treatment of 12 with
10% Pd-C and tenfold excess HCOONH4 in MeOH at reflux for 7 h to
provide compound 1 in 90% yield. However, the debenzylation is quite temp-
erature dependent. The same reaction at room temperature for 15 h failed to
yield any product, whereas at temperatures greater than 1008C, a number of
by-products appeared. Hence, maximum yields of debenzylation can be
obtained when the reaction is carried out in the range of 60–808C. The
total yield of 1 was 34%. This represents a dramatic improvmement in the
overall yield.
The compounds 1, 2, 5–7, and 10–12 were tested for their antiviral
activity against HIV-1 RT using the HIV-antigen detection enzyme-linked
immunosorbent assay (ELISA) method and nevirapine as a reference
compound. Unfortunately, only compound 1 (IC50 ¼ 24 mM) showed activity
against HIV-1 RT, but at a higher concentration than the reference compound
nevirapine (IC50 ¼ 3.6 mM). Other compounds had no activity.
The biological results suggested that these MKC-442 analogs, by introdu-
cing 5-dimethylamino and 6-phenethyl, do not improve the biological activity
and that the distance between the pyrimidine and the phenyl ring is an
important criterion for activity.
EXPERIMENTAL
All reactions were monitored by TLC. NMR spectra were recorded on a JNM-
1
AL-300 NMR spectrometer at 300 MHz for H NMR and 75 MHz for 13C
NMR with TMS as the internal standard. Mass spectra were obtained with
electrospray ionization-time-of-flight (ESI-TOF). Melting points were deter-
mined on an X4-type melting-point apparatus. IR was recorded on an
Avatar 360 FT-IR spectrometer. Elemental analyses were performed by
Vario EL-III and were within +0.4% of the theoretical values. DMF and
CH3CN were dried and freshly distilled over CaH2.
5-Nitro-6-methyluracil (4)
To the solution of P2O5 (1 g, 7.04 mmol) in fuming nitric acid (2.28 mL),
6-methyluracil (3, 1.1 g, 8.7 mmol) was added, and the temperature was kept
colder than 08C with ice/salt. The mixture was stirred for 4 h at 08C and
placed in a refrigerator overnight. The next day, it was poured into icewater,
then filtered and washed to yield the yellow-green solid product 4 (1.21 g,

2426
X. Wang et al.
81%); mp 2908C (dec.). IR (KBr): 3161, 3030, 2846, 1720, 1715, 1516,
1
1359 cm21. H NMR (DMSO-d6): d ¼ 2.30 (s, 3H, CH3), 11.80 (s, 1H, N1-
H), 11.84 (s, 1H, N3-H). ESI-TOF, m/z: 172.15 [M þ H]þ, 194.14 [M þ Na]þ.
1, 3-Dibenzyl-5-nitro-6-phenethyluracil (5)
To the solution of 5-nitro-6-methyluracil 4 (0.4 g, 2.33 mmol) in DMF
(10 mL), NaH (0.3 g, 7.50 mmol, 60% in oil) was added under a nitrogen
atmosphere. The mixture was stirred at room temperature for 1 h, and then
benzyl bromide (10.5 mL, 7.50 mmol) was added. After reaction for 2 h at
room temperature, the mixture was taken up in H2O (25 mL) and extracted
with ethyl acetate. The organic layer was washed with brine, dried over
MgSO4, and concentrated under vacuum to provide the residue, which was
purified by chromatography on silica gel (25% EtOAc–petroleum ether) to
1
give the yellow solid product 5 (0.67 g, 66%); mp 172–1748C. H NMR
(CDCl3): d ¼ 2.80–2.91 (m, 4H, CH2CH2), 5.17 (s, 2H, NCH2Ph), 5.19
(s, 2H, NCH2Ph), 7.09–7.54 (m, 15H, Ph). ESI-TOF, m/z: 442.41
[M þ H]þ. Anal. calcd. for C26H23N3O4 (441.48): C, 70.73; H, 5.25; N,
9.52. Found: C, 70.67; H, 5.14; N, 9.49.
5-Amino-1,3-dibenzyl-6-phenethyluracil (6)
1,3-Dibenzyl-5-nitro-6-phenethyluracil 5 (0.58 g, 1.31 mmol) was dissolved in
MeOH (15 mL) and heated to 508C. After Na2S2O4 (1.0 g, 5.8 mmol) was
added, the mixture was refluxed with stirring for 30 min, then cooled to room
temperature, filtered, and concentrated under reduced pressure to obtain the
resulting oil. After purification by column chromatography (10% MeOH-
1
CHCl3), the product 6 was obtained as a pale yellow oil (0.48 g, 89%). H
NMR (CDCl3): d ¼ 2.25 (m, 2H, NH2), 2.76–2.80 (m, 4H, CH2CH2), 5.09
(s, 2H, NCH2Ph), 5.23 (s, 2H, NCH2Ph), 7.08–7.50 (m, 15H, 3 ꢀ Ar). MS
(EI, 70eV): m/z ¼ 411 [Mþ], 91. Anal. calcd. for C26H25N3O2 (411.50): C,
75.89; H, 6.12; N, 10.22. Found: C, 75.79; H, 6.09; N, 10.12.
1,3-Dibenzyl-5-(N,N-dimethylamino)-6-phenethyl-uracil (7)
Method A
A suspension of compound 6 (0.41 g, 1 mmol) in dry CH3CN (8 mL) was
treated with sodium hydride (82 mg, 2 mmol, 60% in oil) at 08C. Then
methyl iodide (0.13 mL, 2.4 mmol) was added. The reaction mixture was
stirred for ca. 48 h at room temperature and taken up in water (5 mL). After
concentration under reduced pressure, the residue was dissolved in ethyl

1-(Alkyl)-5-dimethylamino-6-phenethyluracils
2427
acetate (15 mL) and washed with water (2 ꢀ 10 mL). The organic layer was
dried over Na2SO4 and evaporated under reduced pressure. After being
purified by column chromatography (5% AcOEt-PE), the product 7 was
obtained (0.13 g, 30%).
Method B
To the solution of 6 (0.41 g, 1 mmol) in dry N,N-dimethyl formamide (DMF)
(5 ml), K2CO3 powder (0.40 g, 2.9 mmol) was added. After stirring for
10 min, methyl iodide (0.13 mL, 2.4 mmol) was added. The reaction
mixture was stirred at room temperature for 6 h and quenched with cold
water (20 mL). The solution was extracted with ethyl acetate (3 ꢀ 15 mL).
The organic layers were collected, dried, and evaporated to furnish the
crude product, which was purified by column chromatography on silica gel
(5% AcOEt-PE) to afford the white solid product 7 (0.17 g, 40%); mp 138–
1408C.
1H NMR (CDCl3): d ¼ 2.73 [s, 6H, N (CH3)2], 2.77–2.97 (m, 4H,
CH2CH2), 5.10 (s, 2H, NCH2Ph), 5.17 (s, 2H, NCH2Ph), 7.09–7.52
(m, 15H, 3 ꢀ Ar). MS (EI, 70 eV): m/z ¼ 439 [Mþ], 348, 91. Anal. calcd.
for C28H29N3O2 (423.55): C, 76.51; H, 6.65; N, 9.56. Found: C, 76.47; H,
6.60; N, 9.45.
5-(N,N-Dimethylamino)-6-phenethyluracil (8) and 1-Benzyl-5-(N,N-
dimethylamino)-6-phenethyl Uracil (2)
To the stirred suspension of 7 (100 mg, 0.22 mmol) and 10% Pd-C (0.3 g) in
dry MeOH, anhydrous NH4COOH (0.26 g, 4.1 mmol) was added. The
resulting mixture was refluxed with stirring, and the reaction was monitored
by TLC. After 3 days, the catalyst was removed by filtration through a
Celitew pad and washed with chloroform (5 mL). The filtrate was concen-
trated under reduced pressure to afford the white solid products 2 and 8,
which were purified by column chromatography (10% MeOH-CHCl3).
Compound 2
1
Yield 39 mg, 51%; mp 147–1488C. H NMR (CDCl3): d ¼ 2.68 [s, 6H, N
CH3)2], 2.83–2.97 (m, 4H, CH2CH2), 5.07 (s, 2H, NCH2Ph), 7.19–7.43
(m, 10H, 2 ꢀ Ar), 10.38 (s, 1H, NH). 13C NMR (CDCl3): d ¼ 30.8, 33.9
(CH2CH2), 43.4 [N (CH3)2], 43.6 (NCH2Ph), 123.6 (C-5), 126.5, 127.5,
128.4, 128.4, 128.7, 136.9, 140.1 (Carom), 150.5 (C-6), 152.8 (C-2), 161.7
(C-4). MS (EI, 70 eV): m/z ¼ 349 [Mþ], 258, 91. Anal. calcd. for
C21H23N3O2 (349.43): C, 72.18; H, 6.63; N, 12.03. Found: C, 72.05; H,
6.51; N, 11.90.

2428
X. Wang et al.
Compound 8
1
Yield 12 mg, 21%; mp 198–2008C. H NMR (DMSO): d ¼ 2.74 [s, 6H, N
(CH3)2], 2.74–2.81 (m, 4H, CH2CH2), 7.19–7.32 (m, 5H, Ar), 10.51
(s, 1H, N1H), 10.72 (s, 1H, N3H). 13C NMR (DMSO): d ¼ 30.1, 33.5
(CH2CH2), 43.2 [N (CH3)2], 121.9 (C-5), 126.2, 128.4, 140.6 (Carom), 150.8
(C-6), 152.2 (C-2), 162.4 (C-4). MS (EI, 70 eV): m/z ¼ 259 [M þ ], 168,
91. Anal. calcd. for C14H17N3O2 (259.30): C, 64.85; H, 6.61; N, 16.21.
Found: C, 64.72; H, 6.50; N, 16.09.
1-(Ethoxymethyl)-5-(N,N-dimethylamino)-6-phen-ethyluracil (1)
To the solution of 8 (30 mg, 0.12 mmol) in dry CH3CN (15 mL), N,O-bis (tri-
methylsilyl) acetamide (BSA) (0.06 mL, 0.24 mmol) was added. After stirring
at room temperature for 15 min, chloromethyl ethyl ether (14 mL, 0.12 mmol)
was added. The reaction mixture was stirred for a further 40 min and then con-
centrated to dryness. The residue was purified by chromatography on silica gel
(5% MeOH-CHCl3) to afford the white solid product 1 (19 mg, 50%); mp
1
142–1438C. H NMR (CDCl3): d ¼ 1.24 (t, J ¼ 6.9 Hz, 3H, CH3), 2.65 [s,
6H, N(CH3)2], 2.8–3.19 (m, 4H, CH2CH2), 3.60 (q, J ¼ 6.9 Hz, 2H,CH2),
5.17 (s, 2H, NCH2O), 7.34–7.23 (m, 5H, Ph), 8.67 (s, 1H, N3-H). ESI-
TOF: m/z ¼ 318.32 [M þ H]þ. Anal. calcd. for C17H23N3O3 (317.38): C,
64.33; H, 7.30; N, 13.24. Found: C, 64.01; H, 7.21; N, 13.04.
1-(Ethoxymethyl)-5-nitro-6-methyluracil (9)
To the suspension of 4 (171 mg, 1.00 mmol) in dry CH3CN (10 mL), BSA
(0.52 mL, 2.08 mmol) was added. After the mixture became clear, chloro-
methyl ethyl ether (115 mL, 1.00 mmol) was added. The reaction mixture
was stirred at room temperature until TLC showed that no more products
were formed. Then the reaction mixture was evaporated in vacuo to afford
9 (126 mg, 55%) as a white solid after purification by column chromatography
1
(5%AcOEt-PE); mp 142–1448C. H NMR (CDCl3): d ¼ 1.25 (t, J ¼ 6.9Hz,
3H, CH3), 2.53 (s, 3H, CH3), 3.67 (q, J ¼ 6.9 Hz, 2H, CH2), 5.41 (s, 2H,
NCH2O), 9.62 (s, 1H, N3-H). ESI-TOF: m/z ¼ 230.21 [M þ H]þ, 252.23
[M þ Na]þ. Anal. calcd. for C8H11N3O5 (229.19): C, 41.92; H, 4.84; N,
18.33. Found: C, 41.80; H, 4.78; N, 18.17.
1-(Ethoxymethyl)-3-benzyl-5-nitro-6-phenylethyl- uracil (10)
The solution of 1-(ethoxymethyl)-5-nitro-6-methyluracil 9 (1.00 g, 4.3 mmol)
in DMF (10 mL) was treated portionwise with NaH (0.36 g, 9.0 mmol, 60% in

1-(Alkyl)-5-dimethylamino-6-phenethyluracils
2429
oil) under a nitrogen atmosphere. The reaction mixture was stirred at room
temperature for 1 h, and then benzyl bromide (13.0 mL, 9.29 mmol) was
slowly added. After reacting for 2 h at room temperature, the mixture was
poured into ice water (25 mL) and concentrated in vacuo to dryness. The
residue was dissolved in CHCl3 (30 mL) and washed with water (12 mL).
The aqueous layer was extracted with CHCl3 (4 ꢀ 10 mL). The combined
organic layer was washed with brine, dried over Mg2SO4, and evaporated to
dryness. The residue was purified and crystallized from EtOAc-PE to give
1
1.50 g (85%) of 10 as a yellow solid; mp 150–1518C. H NMR (CDCl3):
d ¼ 1.24 (t, J ¼ 6.9 Hz, 3H, CH3), 2.91–3.01 (m, 4H, CH2CH2), 3.65
(q, J ¼ 6.9 Hz, 2H, CH2), 5.30 (s, 2H, NCH2Ph), 5.45 (s, 2H, NCH2O),
7.26–7.19 (m, 10H, 2 ꢀ Ar). ESI-TOF-MS: m/z ¼ 410.39 [M þ H]þ,
432.38 [M þ Na]þ. Anal. calcd. for C22H23N3O5 (409.44): C, 64.54; H,
5.66; N, 10.26. Found: C, 64.37; H, 5.57; N, 10.14.
1-(Ethoxymethyl)-3-benzyl-5-amino-6-phenylethyl-uracil (11)
The compound 10 (0.20 g, 0.49 mmol) was dissolved in absolute methanol
(15 mL), and heated to 558C, and then Na2S2O4 (0.4 g, 2.3 mmol) was
added under stirring. The mixture was heated at reflux for 45 min, cooled,
and filtered. The solvent was removed to afford 11 (0.17 g, 94%) as a
yellow oil. 1H NMR (CDCl3): d ¼ 1.15 (t, J ¼ 6.9 Hz, 3H, CH3), 2.21
(m, 2H, NH2), 2.86–2.93 (m, 4H, CH2CH2), 3.80 (q, J ¼ 6.9 Hz, 2H, CH2),
5.27 (s, 2H, NCH2Ph), 5.41 (s, 2H, NCH2O), 7.41–7.94 (m, 10H, 2 ꢀ Ar).
ESI-TOF: m/z ¼ 380.48 [M þ H]þ, 402.49 [M þ Na]þ. Anal. calcd. for
C22H25N3O3 (379.45): C, 69.64; H, 6.64; N, 11.07. Found: C, 69.52; H,
6.59; N, 10.96.
1-(Ethoxymethyl)-3-benzyl-5-(N,N-dimethylamino)-6-
phenylethyluracil (12)
Compound 11 (1.00 g, 2.60 mmol) was dissolved in 10 mL of dry CH3CN,
and sodium hydride (0.22 g, 5.50 mmol, 60% in oil) was added portionwise.
After reacting for 1 h at room temperature, methyl iodide (0.74 g,
5.2 mmol) was slowly added to the mixture and stirred for 36 h at room temp-
erature. The reaction mixture was poured into water (15 mL) and concentrated
in vacuo to dryness. The residue was dissolved in AcOEt (20 mL) and washed
with water (10 mL). The aqueous layer was extracted with AcOEt
(2 ꢀ 25 mL). The combined organic phase was washed with brine, dried
over MgSO4, and evaporated under reduced pressure to give the product 12
(0.92 g, 87%) after purification by silica column chromatography
1
(10%AcOEt-PE). IR (KBr): 2933, 1702, 1652, 1446, 1096, 701cm21. H
NMR (CDCl3): d ¼ 1.21 (t, J ¼ 6.9 Hz, 3H, CH3), 2.73 [s, 6H, N(CH3)2],

2430
X. Wang et al.
2.83–2.91 (m, 4H, CH2CH2), 3.62 (q, J ¼ 6.9 Hz, 2H, CH2), 5.12 (s, 2H,
CH2), 5.30 (s, 2H, CH2), 7.23–7.45 (m, 10H, 2 ꢀ Ar). 13C NMR (CDCl3):
d ¼ 15.0 (CH3), 29.7, 35.1 (CH2CH2), 43.4 [N(CH3)2], 44.3 (NCH2Ph), 64.9
(OCH2), 74.0 (NCH2O), 119.7 (C-5), 124.6, 126.5, 127.4, 128.2, 128.3,
128.6, 128.9, 137.0 (Carom), 140.5 (C-6), 152.1 (C-2), 160.7 (C-4). ESI-
TOF: m/z ¼ 408.52 [M þ H]þ, 430.53 [M þ Na]þ. Anal. calcd. for
C24H29N3O3 (407.51): C, 70.74; H, 7.17; N, 10.31. Found: C, 70.69; H,
7.08; N, 10.20.
1-(Ethoxymethyl)-5-(N,N-dimethylamino)-6-phenylethyluracil (1)
Compound 12 (55 mg, 0.14 mmol) was dissolved in absolute ethanol (10 mL)
and HCO2NH4 (0.20 g, 3.20 mmol) and 10% Pd/C (0.16 g) were added to the
clear solution. The mixture was heated to reflux for 7 h. It was then cooled to
room temperature, filtrated through a Celitew pad, and washed extensively
with methanol. The solvent was removed under reduced pressure to afford 1
(40 mg, 90%) as a white solid product, which was purified by column chrom-
atography (5% MeOH-CHCl3); mp 143–1448C. IR (KBr): 3024, 1708, 1660,
1459, 1084cm21. 1H NMR (CDCl3): d ¼ 1.21 (t, J ¼ 6.9 Hz, 3H, CH3), 2.69
[s, 6H, N(CH3)2], 2.87–2.98 (m, 4H, CH2CH2), 3.57 (q, J ¼ 6.9 Hz, 2H,
CH2), 5.20 (s, 2H, NCH2O), 7.17–7.29 (m, 5H, Ph), 8.61 (s, 1H, N3-H).
ESI-TOF: m/z ¼ 318.35 [M þ H]þ, 340.32 [M þ Na]þ. Anal. calcd. for
C17H23N3O3 (317.38): C, 64.33; H, 7.30; N, 13.24. Found: C, 64.11; H,
7.19; N, 13.07.
ACKNOWLEDGMENTS
We thank the National Science Foundation of China and the 985 Program of
the Ministry of Education of China for financial support.
REFERENCES
1. De Clercq, E. Rev. Med. Viral. 2000, 10, 255.
2. Baba, M.; Tanaka, H.; De Clercq, E.; Pauwels, R.; Balzarini, J.; Schols, D.;
Nakashima, H.; Perno, C. F.; Walker, R. T.; Miyasaka, T. Biochem. Biophys.
Res. Commun. 1989, 165, 1375.
3. Miyasaka, T.; Tanaka, H.; Baba, M.; Hayakawa, H.; Walker, R. T.; Balzarini, J.;
De Clercq, E. J. Med. Chem. 1989, 32, 2507.
4. Tanaka, H.; Takashima, H.; Ubasawa, M.; Sekiya, K.; Inouye, N.; Baba, M.;
Shiro, S.; Walker, R. T.; De Clercq, E. J. Med. Chem. 1995, 38, 2860.
5. (a) Tanaka, H.; Baba, M.; Hayakawa, H.; Sakamaki, T.; Miyasaka, T.;
Ubasawa, M.; Takashima, H.; Sekiya, K.; Nitta, I.; Shigeta, S.; Walker, R. T.;
Balzarini, J.; De Clercq, E. J. Med. Chem. 1991, 34, 349; (b) Hopkins, A. L.;

1-(Alkyl)-5-dimethylamino-6-phenethyluracils
2431
Ren, J.; Esnouf, R. M.; Willcox, B. E.; Jones, E. Y.; Ross, C.; Miyasaka, T.;
Walker, R. T.; Tanaka, H.; Stammers, D. K.; Stuart, D. I. J. Med. Chem. 1996,
39, 1589.
6. Han, P.; Wang, X. W.; Zhang, Z. L.; Chen, L. L.; Liu, J. Y.; Chin. J. Org. Chem.
2003, 23, 1111 (in Chinese).
7. (a) Kadam, S. M.; Nayak, S. K.; Banerji, A. Tetrahedron Lett. 1992, 33,
5129–5132; (b) Lohse, O.; Beutler, U.; Fu¨nfschilling, P.; Furet, P.; France, J.
Tetrahedron Lett. 2001, 42, 385.
8. (a) Palomo, C.; Aizpurua, J. M.; Garcia, J. M.; Iturburu, M.; Odriozola, J. M.
J. Org. Chem. 1994, 59 (18), 5184–5188; (b) Renard, A.; Kotera, M.;
Lhomme, J. Tetrahedron Lett. 1998, 39, 3129; (c) Yoda, H.; Nakajima, T.;
Takabe, K. Synlett 1997, 911.
9. (a) Brook, G. M.; Mohammed, S.; Whiting, M. C. J. Chem. Soc., Chem. Commun.
1997, 1511; (b) Thomas, J. T.; Terry, A. L.; Catherine, M. W.; Susan, F. B.;
Steven, D. Y.; William, M. S.; William, C. L.; Mark, E. G.; Julie, A. O.;
Richard, G. B.; Carl, F.; William, A. S.; Emilio, A. E.; Joel, R. H.; Paul, S. A.
J. Med. Chem. 1994, 37, 2437.
10. Nitya, G. K.; Robert, P. H.; Stephen, J. H. Tetrahedron Lett. 1980, 21, 1109.
11. (a) Zimmerman, M. N.; Nemeroff, N. H.; Bock, C. W.; Bhat, K. L. Heterocycles
2000, 53, 205; (b) Holschbach, M. H.; Fein, T.; Krummeich, C.; Lewis, R. G.;
Wutz, W.; Schwabe, U.; Unterlugauer, D.; Olsson, R. A. J. Med. Chem. 1998,
41, 555; (c) Ram, S.; Spicer, L. D. Tetrahedron Lett. 1987, 28, 515.
12. (a) Tucker, T. J.; Lyle, T. A.; Wiscount, C. M.; Britcher, S. F.; Young, S. D.;
Sander, W. M.; Lumma, W. C.; Goldman, M. E.; O’Brien, J. A. J. Med. Chem.
1994, 37, 2437; (b) Danel, K.; Larsen, E.; Pedersen, E. B. Synthesis 1995, 934.