Facile alternative synthesis of 1-alkyl-5-alkylamino-6-phenethyluracils

Article abstract of DOI:10.1080/00397910802654765

A short alternative synthesis of 1-alkyl-5-alkylamino-6-phenethyluracil is described in 47% overall yield of 1a via five steps starting from commercially available 6-methyluracil.

Full text of DOI:10.1080/00397910802654765

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Facile Alternative Synthesis
of 1-Alkyl-5-alkylamino-6-
phenethyluracils
Zhili Zhang a , Zhijian Cheng b , Xiaoyan Ma a ,
Xiaowei Wang a & Junyi Liu a c
a Department of Chemical Biology, School of
Pharmaceutical Sciences, Peking University, Beijing,
China
b Department of Chemistry, College of Jiujiang,
Jiujiang, China
c State Key Laboratory of Natural and Biomimetic
Drug, Peking University, Beijing, China
Version of record first published: 01 Jun 2009.
To cite this article: Zhili Zhang , Zhijian Cheng , Xiaoyan Ma , Xiaowei Wang & Junyi
Liu (2009): Facile Alternative Synthesis of 1-Alkyl-5-alkylamino-6-phenethyluracils,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 39:13, 2310-2316
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Synthetic Communications1, 39: 2310–2316, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802654765
Facile Alternative Synthesis of 1-Alkyl-5-
alkylamino-6-phenethyluracils
Zhili Zhang,1 Zhijian Cheng,2 Xiaoyan Ma,1 Xiaowei Wang,1
and Junyi Liu1,3
1Department of Chemical Biology, School of Pharmaceutical Sciences,
Peking University, Beijing, China
2Department of Chemistry, College of Jiujiang, Jiujiang, China
3State Key Laboratory of Natural and Biomimetic Drug,
Peking University, Beijing, China
Abstract: A short alternative synthesis of 1-alkyl-5-alkylamino-6-phenethyluracil
is described in 47% overall yield of 1a via five steps starting from commercially
available 6-methyluracil.
Keywords: 1,5-Disubstituted-6-phenethyluracil, heterocycles, synthesis
Pyrimidine and its derivatives are important classes of biologically active
heterocyclic compounds. Various 5-alkyl substituted derivatives of uracil
have been synthesized for both anticancer and antiviral properties. Nota-
ble among them is 6-benzyl-1-(benzyloxymethyl)-5-isopropyluracil
(TNK651) (Fig. 1), which is one of the most potent agents effective
against HIV-1 reverse transcriptase (HIV-1 RT).[1] Currently, research
work in our laboratory has concerned access to 1,5-dialkylsubstituted-
6-phenethyluracils I and II (Fig. 1) and their derivatives as potent
nonnucleoside HIV-1 RT inhibitors.[2,3] In a previous publication, we
described the preparation of 1-alkyl-5-dimethylamino-6-phenethylura-
cil[2] from 6-methyluracil via six-stage reactions in 34% total yield.
Received August 25, 2008.
Address correspondence to Junyi Liu, Department of Chemical Biology,
School of Pharmaceutical Sciences, Peking University, Beijing 100083, China.
E-mail: lilybmu@bjmu.edu.cn
2310

1-Alkyl-5-alkylamino-6-phenethyluracils
2311
Figure 1. Structures of TNK651, I and II.
However, the both procedures involve six synthetic steps[2] from
6-methyluracil as the starting material and limit a number of other N5-
substituted reactions. Herein, a shorter (five-step), facile, alternative
synthesis of the title compounds (Scheme 1) is reported. The total yield
of 1a was 47%, which represents a big improvement in overall yield.
First, we investigated the halogenations of 6-methyluracil (2). Initial
attempts to get access to the compounds 3 using ICl-MeOH[4,5] failed or
[6]
led to poor yields. However, treatment of 2 with PbO2-HOAc-I2 at
Scheme 1. Reagents and conditions: (a) PbO2, HOAc, I2, 50ꢀC, 3 h; (b)
CICH2OCH2CH3, BSA, CH3CN, rt; (c) PhCH2Br, NaH, DMF; (d) (CH3)2NH
or CH3NH2; and (e) HCOONH4, Pd=C, MeOH.

2312
Z. Zhang et al.
50ꢀC provided the 5-iodo-6-methyluracil 3 in 94% yield after purification
by column chromatography. Compound 3 was transformed into 1-ethox-
ymethyluracil (4) via reaction with N,O-bis(trimethylsilyl)acetamide
(BSA) and chloromethylethyl ether in CH3CN. Treatment of 3 or 4 with
benzyl bromide and NaH in tetrahydrofuran (THF) gave 1,3-dibenzyl-5-
iodo-6-phenethyluracil (5b) in 82–85% yield and 1-ethoxymethyl-3-
benzyl-5-iodo-6-phenethyluracil (5a) in 87% yield. Compound 5a was
transformed into 1-ethoxymethyl-3-benzyl-5-(N,N-dimethylamino)-6-
phenethyluracil (6a) via replacement of iodo by dimethylamine under
reflux. Compound 5b was transformed into 1,3-dibenzyl-5-(N,N-
dimethylamino)-6-phenethyluracil (6b) and 1,3-dibenzyl-5-(N-methyla-
mino)-6-phenethyluracil (6c) with the reaction of dimethylamine or
methylamine, respectively. Compounds 6a, 6b, and 6c can be smoothly
deprotected into title compounds 1a, 1b, and 1c in 53–87% yield using
HCOONH4-Pd=C in MeOH under reflux.
All the compounds were characterized by 1H NMR, mass, and infra-
red (IR) spectral data, and the final compound 1b was additionally
characterized by 13C NMR.
In conclusion, we have developed a convenient method to synthesize
N5-substituted-6-phenethyluracil. This route is a shorter sequence than
the previously published procedure for the compounds 1a, 1b, and 1c
and their derivatives, and will have broad application when these kinds
of N5-substituted pyrimidine compounds are explored for therapeutic
utilities.
EXPERIMENTAL
Melting points (uncorrected) were determined with an X4-type apparatus.
1H and 13C NMR spectra were recorded on a JNM-AL-300 or a Varian
Inova-500 spectrometer using tetramethylsilane (TMS) as an internal
standard. Mass spectra (MS) were recorded on a VG-ZAB-HS spectro-
meter. IR spectra were recorded with Avatar 360 Fourier transform
(FT)–IR and are reported in centimetersꢁ1. Silica gel (0.40–0.64 mm)
was used for column chromatography.
5-Iodo-6-methyl uracil (3)
PbO2 (66 mg, 0.28 mmol) was added in portions to the suspension of
6-methyluracil (63 mg, 0.5 mmol) in glacial HOAc (15 mL) while stirring,
and then I2 (70 mg, 0.28 mmol) was added. The reaction mixture was
heated to 50ꢀC for 3 h. The PbO2 was filtered, and then the filtrate was
diluted with H2O (80 mL). The precipitate was isolated, washed with

1-Alkyl-5-alkylamino-6-phenethyluracils
2313
water and ether, then dried in vacuo to give a solid (118 mg, 94%),
1
mp > 300ꢀC. H NMR (300 MHz, DMSO-d6): d ¼ 11.40 (s, 1H, NH),
11.54 (s, 1H, NH), 2.64 (s, 3H, CH3). EIMS: m=z ¼ 257 [M þ 1]þ.
1-Ethoxymethyl-5-iodo-6-methyluracil (4)
BSA (0.37 mL, 1.24 mmol) was added to the solution of 5-iodo-6-
methyluracil 3 (120 mg, 0.47 mmol) in CH3CN (15 mL). The solution
was stirred at rt for 50 min, then the ClCH2OCH2CH3 (45 mL, 0.48 mmol)
and LiI (50 mg) were added. The resulting mixture was stirred at rt for
75 min and quenched by addition of NaHCO3. The solution was
extracted with EtOAc (3 ꢂ 15 mL), and the combined extracts were
washed with H2O and dried over MgSO4. The solvent was removed to
give the crude product, which was purified by column chromatograph
(EtOAc=petrol. 1:1) to yield the product (110 mg, 73%), mp 163ꢀC
1
(dec). H NMR (300 MHz, CDCl3): d ¼ 8.30 (s, 1H, NH), 5.24 (s, 2H,
CH2), 3.65 (q, J ¼ 7.2 Hz, CH2), 2.51 (s, 3H, CH3), 1.22 (t, J ¼ 7.0 Hz,
3H, CH3). EIMS: m=z ¼ 314 [Mþ].
1-Ethoxymethyl-3-benzyl-5-iodo-6-phenethyluracil (5a)
NaH (27 mg, 0.64 mmol, 60% in oil) was added to a solution of 1-ethoxy-
methyl-5-iodo-6-methyluracil 4 (100 mg, 0.32 mmol) in DMF (10 mL),
portionwise under N2. The mixture was stirred at rt for 1 h, and benzyl-
bromide (1.16 mL, 0.8 mmol) was slowly added. The resulting mixture
was stirred for 2–2.5 h, and water (20 mL) was added. After it was con-
centrated to dryness, the residue was dissolved in CH2Cl2 (20 mL) and
washed with water. The aqueous layer was extracted with CH2Cl2. The
combined organic layer was washed with brine, dried over Na2SO4,
and evaporated to give the crude product, which was chromatographed
(EtOAc–petrol. 1:2) to give 137 mg (87%) of 5a, mp 173–175ꢀC. 1H
NMR (300 MHz, CDCl3): d ¼ 1.23 (t, J ¼ 7.0 Hz, 3H, CH3), 2.93–3.04
(m, 4H, CH2CH2), 3.63 (q, J ¼ 7.0 Hz, 2H, CH2), 5.32 (s, 2H, CH2Ph),
5.45 (s, 2H, CH2O), 7.18–7.25 (m, 10H, 2Ar). EIMS: m=z ¼ 491 [M þ 1]þ.
1,3-Dibenzyl-5-iodo-6-phenethyluracil (5b)
NaH (110 mg, 2.73 mmol, 60% in oil) was added to the solution of 5-iodo-
6-methyluracil 3 (200 mg, 0.78 mmol) in dimethylformamide (DMF)
under N2. The reaction mixture was stirred at rt for 1 h, and then benzyl-
bromide (3.6 mL, 2.57 mmol) was added. After reaction for 2 h at rt, the

2314
Z. Zhang et al.
mixture was poured into H2O (25 mL) and extracted with EtOAc. The
combined organic layer was washed with brine, dried over Na2SO4,
and concentrated to give the residue, which was purified by chromatogra-
phy on silica gel (EtOAc–petrol. ¼ 1:3) to give the solid 5b (340 mg, 82%),
mp 114ꢀC (dec). 1H NMR (300 MHz, CDCl3): d ¼ 2.81–293 (m, 4H,
CH2CH2), 5.16 (s, 2H, CH2Ph), 5.19 (s, 2H, CH2Ph), 7.14–7.62 (m,
15H, 3Ph). EIMS: m=z ¼ 523 [M þ 1]þ.
1-Ethoxymethyl-3-benzyl-5-(N,N-dimethylamino)-6-phenethyluracil (6a)
The excess (CH3)2NH (4 mL) was added to the solution of compound 5a
(500 mg, 1.02mmol) in THF (1 mL). Then the solution was heated to 60ꢀC
for 30–35 h. After the reaction mixture was cooled to rt, H2O (10 mL) was
added and extracted with EtOAc (3ꢂ 15mL). The organic layer was
washed with H2O and dried over Na2SO4. The solvent was removed to give
the product (oil) (380mg, 90%) after purification by column chromatogra-
phy (petrol.–EtOAc ¼ 9:1). IR (KBr): 2935, 1705, 1655, 1447, 1095,
702 cmꢁ1
.
1H NMR (300MHz, CDCl3): d ¼ 1.23 (t, J ¼ 6.9 Hz, 3H,
CH3), 2.71 (s, 6H, (CH3)2N), 2.80–2.89 (m, 4H, CH2CH2), 3.64 (q,
J ¼ 6.9 Hz, 2H, CH2), 5.12 (s, 2H, CH2), 5.30 (s, 2H, CH2), 7.23–7.45
(m, 10H, 2Ar). ESI-TOF: m=z ¼ 408.52 [Mþ 1]þ, 430.53 [MþNa]þ.
1,3-Dibenzyl-5-(N,N-dimethylamino)-6-phenethyluracil (6b)
The general procedure was similar to 6a. Yield 340 mg (80%), mp 139–
141ꢀC.[2] 1H NMR (300 MHz, CDCl3): d ¼ 2.71 (s, 6H, N(CH3)2), 2.79–
3.01 (m, 4H, CH2CH2), 5.12 (s, 2H, NCH2Ph), 5.17 (s, 2H, NCH2Ph),
7.19–7.54 (m, 15H, 3Ar). EIMS: m=z ¼ 439 [Mþ].
1,3-Dibenzyl-5-(N-methylamino)-6-phenethyluracil (6c)
The procedure was similar to 6a. Yield 310 mg (76%), mp 146ꢀC (dec). 1H
NMR (300 MHz, CDCl3): d ¼ 2.63 (s, 3H, CH3), 2.74–2.97 (m, 4H,
CH2CH2Ph), 5.01 (s, 2H, CH2Ph), 5.29 (s, 2H, CH2Ph), 7.06–7.60 (m,
15H, 3Ar). EIMS: m=z ¼ 425 [Mþ].
1-Ethoxymethyl-5-(N,N-dimethylamino)-6-phenethyluracil (1a)
HCO2NH4 (200 mg, 3.20 mmol) and 10% Pd=C (160 mg) were added to
the solution of compound 6a (55 mg, 0.11 mmol) in ethanol (12 mL).

1-Alkyl-5-alkylamino-6-phenethyluracils
2315
The reaction mixture was heated under reflux for 7–7.5 h, then cooled to
rt, filtered, and concentrated under reduced pressure to give 7a, which
was purified by column chromatography (CHCl3–MeOH ¼ 95:5) to give
31 mg (87%), mp 142–143ꢀC.[2] IR (KRr): 3024, 1709, 1665, 1460,
1082 cmꢁ1
.
1H NMR (300 MHz, CDCl3): d ¼ 1.24 (t, J ¼ 6.9 Hz, 3H,
CH3), 2.67 (s, 6H, N(CH3)2), 2.88–3.16 (m, 4H, CH2CH2), 3.62 (q,
J ¼ 6.9 Hz, 2H, CH2), 5.21 (s, 2H, CH2O), 7.19–7.31 (m, 5H, Ph), 8.60
(s, H, N3-H). ESI-TOF: m=z ¼ 318.32 [M þ 1]þ, 340.35 [MþNa]þ.
1-Benzyl-5-(N,N-dimethylamino)-6-phenethyluracil (1b)
Pd=C (300 mg) and HCOONH4 (270 mg, 4.1 mmol) were added to the
solution of compound 6b (100 mg, 0.22 mmol) in dry MeOH. The mixture
was refluxed for 3 days and then cooled to rt. The catalyst was filtered
through a celite pad, washed with CHCl3, and concentrated under
reduced pressure to give solid 1b, which was purified by silica column
chromatography (CHCl3–MeOH ¼ 9:1). Yield 43 mg (53%), mp 147–
148ꢀC.[2] 1H NMR (300 MHz, CDCl3): d ¼ 2.64 (s, 6H, CH3), 2.80–2.94
(m, 4H, CH2CH2), 5.10 (s, 2H, CH2Ph), 7.21–7.46 (m, 10H, 2Ph),
10.42 (s, 1H, NH). 13C NMR (75 MHz, CDCl3): 31, 33.9, 43.1, 43.5,
124, 126.7, 127.3, 128.2, 128.7, 137.2, 140.7, 150.7, 153.1, 161.8. EIMS:
m=z ¼ 349 [Mþ].
1-Benzyl-5-(N-methylamino)-6-phenethyluracil (1c)
1
The general procedure was similar to 1b. H NMR (300 MHz, CDCl3):
d ¼ 2.59 (s, 3H, CH3), 2.81–2.95 (m, 4H, CH2CH2Ph), 3.26 (s, 1H,
NH), 5.12 (s, 2H, CH2Ph), 7.51–7.27 (m, 10H, 2Ar), 9.27 (s, 1H, N3H).
EIMS: m=z ¼ 336 [M þ 1]þ.
ACKNOWLEDGMENTS
We thank the National Sciences Foundation of China (No. 20672008)
and 985 Program of the Ministry of Education of China for financial
support.
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