Facile route for the synthesis of nucleobase analogs

Article abstract of DOI:10.1080/00397910802374083

Various nucleobases, 5-heteroaryl substituted 2,4-alkoxy, and/or aryloxy pyrimidines were prepared in an easy method. Copyright Taylor & Francis Group, LLC.

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Facile Route for the Synthesis
of Nucleobase Analogs
Vijayalaxmi Amareshwar a
a Department of Chemistry , Gulbarga University ,
Gulbarga, Karnataka, India
Published online: 22 Dec 2008.
To cite this article: Vijayalaxmi Amareshwar (2008) Facile Route for the Synthesis
of Nucleobase Analogs, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 39:2, 342-346, DOI:
10.1080/00397910802374083
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Synthetic Communications1, 39: 342–346, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910802374083
Facile Route for the Synthesis
of Nucleobase Analogs
Vijayalaxmi Amareshwar
Department of Chemistry, Gulbarga University, Gulbarga, Karnataka, India
Abstract: Various nucleobases, 5-heteroaryl substituted 2,4-alkoxy, and=or
aryloxy pyrimidines were prepared in an easy method.
Keywords: 5-Heteroaryl-2,4-alkoxy pyrimidines, 5-heteroaryl-2,4-aryloxy pyrimi-
dines, nucleobases
INTRODUCTION
Goudgaon and coworkers prepared 5-phenylthio-2,4-bis(benzyloxy)-
pyrimidine starting from 5-bromouracil (Scheme 1).[1] This method requi-
red the use of reagents such as organilithiums and diphenyldiselenide. In
addition, the metal halogen exchange reaction of their scheme was carried
out and at ꢀ80 ꢁC. We have designed a simple and inexpensive synthesis
for 5-phenylthio-2,4-bis(benzyloxy)pyrimidine.
RESULTS AND DISCUSSION
Reaction of 5-chlorouracil with thiophenol in ethylene glycol in the
presence of anhydrous potassium carbonate at 130–140 ꢁC for 2 h
followed by cooling to room temperature furnished 5-phenylthiouracil
as a white crystalline solid. Formation of this compound was proposed
by the presence of aromatic protons at 7.1–7.4 as a multiple and the char-
acteristic C-6 proton as a singlet at 7.8 in 1H NMR spectrum. Reaction of
Received March 23, 2008.
Address correspondence to Vijayalaxmi Amareshwar, Research and Develop-
ment, 1=318 Kulkurai Street, Seevarum, Thoraipakkam, Chennai 600096, India.
E-mail: vijuorgchem@rediffmail.com
342

Synthesis of Nucleobases
343
Scheme 1. Bn ¼ C6H5CH2.
5-phenylthiouracil with excess phosphorous oxychloride under reflux for
6 h gave 5-phenylthio-2,4-dichloropyrimidine in 86% yield. The inter-
mediate can be the key intermediate for the synthesis of various alkoxy
and aryloxy-substituted derivatives (Scheme 2). On treatment with sodium
methoxide, sodium ethoxide, sodium isopropoxide, and sodium benzyl-
ate, compound 2 gave the corresponding 5-phenylthio-2,4-alkoxy or
aryloxypyrimidines (3 to 6) in 50–75% yields. These compounds were
1
confirmed by spectroscopic data such as H NMR, elemental analysis,
and mass spectra.
EXPERIMENTAL
Melting points were recorded on open capillary tubes and are uncor-
rected. Experiments were monitored using thin-layer chromatography
(TLC) on glass plates precoated with silica gel. Column chromatography,
employing silica gel (60–200 mesh) was used for the purification of
the crude products. 1H NMR spectra were recorded on a DRX av
Scheme 2. 3, R ¼ CH3; 4, R ¼ OCH2CH3; 5, R ¼ CH(CH)3; 6, R ¼ CH2C6H5.

344
V. Amareshwar
400-MHz spectrometer. Mass spectrum was recorded on a Shimandzu
2010A liquid chromatography mass spectrometer (LC=MS).
Synthesis of 5-Phenylthiouracil (1)
A mixture of 5-chlorouracil (3.66 g, 0.025 mol), thiophenol (3.3 g,
0.03 mol), and potassium carbonate (2.45 g, 0.025 mol) in ethylene glycol
(40 ml) was heated to 130–140 ꢁC for 2 h. A clear solution was formed,
which solidified to a white crystalline mass upon cooling. This mass was
dissolved in 200 ml of dilute sodium hydroxide solution. Upon neutraliza-
tion with acetic acid, a white precipitate formed, which was filtered, and
the solid was washed with acetone and ether. The solid obtained was
recrystallized from ethanol to give the title compound. Yield 3.5 g
ꢁ
1
(71%), mp 271–273 C. H NMR (CDCl3) d 7.1–7.4 (m, 5H, SPh), 7.8
(s, 1H, H-6), 6.1 (s, 1H, NH-1), 10.2 (s, 1H, NH-3). LCMS (positive
mode): m=z 221 (M þ 1)þ.
Synthesis of 5-Phenylthio-2,4-dichloropyrimidine (2)
A mixture of 5-phenylthiouracil (3 g, 0.0125 mol) and phosphorous oxy-
chloride (12.2 ml, 0.125 mol) was refluxed for 3 h. Excess phosphorous
oxychloride was removed under reduced pressure, and the mixture was
treated with ice water. The separated solid was extracted with ether
(3 ꢂ 50 ml) and washed with 5% sodium bicarbonate solution (2 ꢂ 50 ml).
The ether layer was collected and dried over anhydrous magnesium sul-
phate. Evaporation of the ꢁsolvent furnished the desired compound 2.
1
Yield 3 g (86%), mp 69–71 C, Rf 0.66 (ethyl acetate–hexane ¼ 1:10). H
NMR (CDCl3) d 7.2–7.6 (m, 5H, SPh), 7.9 (s, 1H, H-6). Anal. calcd. for
C10H6N2SCl2: C, 46.91; H, 2.43; N, 10.94; S, 12.88. Found: C, 46.45; H,
2.36; N, 10.60; S, 12.39. LCMS (positive mode): m=z 258 (M þ 1)þ.
Synthesis of 5-Phenylthio-2,4-dimethoxypyrimidine (3)
Small pieces of sodium metal (0.22 g, 0.01 mol) were added to 5 ml of dry
methanol with stirring in an inert atmosphere. All the sodium metal
dissolved. A solution of 5-phenylthio-2,4-dichloropyrimidine (2) (1.26 g,
0.005 mol) in toluene (20 ml) was added to the reaction mixture and
stirred overnight at room temperature. The precipitate that formed
during the reaction was filtered and washed with toluene. Filtrate was
collected, evaporated under reduced pressure, and recrystallized from
80% ethanol to give pure compound 3 as a white crystalline solid. Yield

Synthesis of Nucleobases
345
ꢁ
1
750 mg (61%), mp 67–69 C. Rf 0.75 (methanol–chloroform ¼ 1:3). H
NMR (CDCl3) d 7.1–7.3 (m, 5H, SPh), 4.0 (s, 3H, OCH3-2), 4.1 (s, 3H
OCH3-4), 8.3 (s, 1H, H-6). Anal. calcd. for C12H12N2O2S: C, 58.04; H,
4.87; N, 11.28; S, 12.91. Found: C, 57.69; H, 5.07; N, 11.26; S, 13.12.
LCMS (positive mode): m=z 249 (M þ 1)þ.
Synthesis of 5-Phenylthio-2,4-diethoxypyrimidine (4)
Reaction of 5-phenylthio-2,4-diethoxypyrimidine (2) (2.56 g, 0.01 mol) in
toluene (40 ml) with sodiumethoxide (0.44 g of sodium metal dissolved in
6 ml of dry ethanol) as described for the preparation of 5-phenylthio-2,4-
dimethoxypyrimidine (3) gave the title compound 4 in the form of a semi-
solid. Yield 1.5 g (61%), Rf 0.878 (methanol–chloroform ¼ 1:3), 1H NMR
(CDCl3) d 7.0–7.2 (m, 5H, Sph), 1.2–1.6 (t, 6H, OCH3-2 and OCH3-4),
4.3–4.4 (q, 4H, OCH2-2 and OCH2-4), 8.2 (s, 1H, H-6). Anal. calcd.
for C14H16N2O2S: C, 60.84; H, 5.84; N, 10.14; S, 11.58. Found: C,
60.96; H, 6.13; N, 9.98; S, 11.26. LCMS (positive mode): m=z 277
(M þ 1)þ.
Synthesis of 5-Phenylthio-2,4-di(iso-propoxy)pyrimidine (5)
Reaction of 5-phenylthio-2,4-dichloropyrimidine (2) (1.26 g, 0.005 mol) in
toluene (20 ml) with sodiumisopropoxide (0.22 g of sodium metal dis-
solved in 12 ml of dry isopropyl alcohol) as described for the preparation
of 5-phenylthio-2,4-dimethoxypyrimidine (3) gave the title compound 5
in form of a semisolid. Yield 700 mg (47%), Rf 0.574 (ethyl acetate–
hexane ¼ 1:10), 1H NMR (CDCl3) d 7.0–7.2 (m, 5H, Sph), 1.20–1.23
(d, 6H, OCH3-2), 1.38–1.41 (d, 6H, OCH3-4), 1.6 (s, 1H, CH-2), 2.2 (s,
1H, CH-4), 8.3 (s, 1H, H-6). Anal. calcd. for C16H20N2O2S: C, 63.13;
H, 6.62; N, 9.20; S, 10.53. Found: C, 63.15; H, 6.69; N, 9.15; S, 10.62.
LCMS (positive mode): m=z 305 (M þ 1)þ.
Synthesis of 5-Phenylthio-2,4-bis(benzyloxy)pyrimidine (6)
A stirred solution of benzyl alcohol (4.32 g, 0.04 mol) in toluene (40 ml)
was treated with 60% w=w sodium hydride in oil (0.82 g, 0.04 mol)
under a nitrogen atmosphere. The mixture was warmed to 55–60 ꢁC
for 30 min to facilitate the formation of sodium salt. After all the
sodium hydride had reacted, the suspension was cooled, and a solution
of 5-phenylthio-2,4-dichloropyrimidine (2) (2.56 g, 0.01 mol) in toluene
(20 ml) was added slowly at room temperature. After stirring overnight

346
V. Amareshwar
at room temperature, the precipitate of sodium chloride was filtered and
the solid was washed with toluene. The filtrate was then evaporated
under reduced pressure, and the crude compound was recrystallized
from ethanol, furnishing the title compound 6. Yield 3.5 g (77%), mp
62–64 ꢁC, Rf 0.41 (ethyl acetate–hexane ¼ 1:10). 1H NMR (CDCl3) d
7.1–7.2 (m, 5H, SPh), 7.2–7.3 (m, 5H, C6H5-2), 7.4–7.5 (m, 5H), 5.4
(s, 4H, C6H5-4), 8.3 (s, 1H H-6). Anal. calcd. for C24H20N2O2S: C,
71.98; H, 5.02; N, 6.99; S, 8.01. Found: C, 71.92; H, 5.06; N, 6.10; S,
7.92. LCMS (positive mode): m=z 401 (M þ 1)þ.
REFERENCE
1. Goudgaon, N. M.; Naguib, F. N. M.; El Kouni, M. H.; Schinazi, R. F.
Phenylselenenyl- and phenylthio-substituted pyrimidines as inhibitors of dihy-
drouracil dehydrogenase and uridine phosphorylase. J. Med. Chem. 1993, 36,
4250–4254.