Convenient synthesis of 5-aryl uracils

Article abstract of DOI:10.1080/00397910701575319

A convenient one-step synthesis of 5-aryl uracils has been developed. The procedure involves heating ethyl 3-hydroxy-2-arylpropenate with urea at 130°C, followed by base-catalyzed cyclization. The method is simple and high yielding. Copyright Taylor & Fra

Full text of DOI:10.1080/00397910701575319

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Convenient Synthesis of 5‐Aryl Uracils
M. Monzur Morshed a , Qinwei Wang a , Shahidul Islam a & M. Mahmun
Hossain a
a Department of Chemistry and Biochemistry, University of
Wisconsin—Milwaukee, Milwaukee, Wisconsin, USA
Version of record first published: 10 Dec 2007.
To cite this article: M. Monzur Morshed, Qinwei Wang, Shahidul Islam & M. Mahmun Hossain (2007):
Convenient Synthesis of 5‐Aryl Uracils, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 37:23, 4173-4181
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Synthetic Communicationsw, 37: 4173–4181, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701575319
Convenient Synthesis of 5-Aryl Uracils
M. Monzur Morshed, Qinwei Wang, Shahidul Islam,
and M. Mahmun Hossain
Department of Chemistry and Biochemistry, University of Wisconsin—
Milwaukee, Milwaukee, Wisconsin, USA
Abstract: A convenient one-step synthesis of 5-aryl uracils has been developed. The
procedure involves heating ethyl 3-hydroxy-2-arylpropenate with urea at 1308C,
followed by base-catalyzed cyclization. The method is simple and high yielding.
Keywords: arylpropenate, uracil, urea
5-Aryl uracils are key precursors in the synthesis of pyrimidine nucleosides[1,2]
(cytidine analogs, Fig. 1), which when substituted at the 5-position represent
an important class of biologically active compounds. Tegafur-uracil, for
example, is a well-known chemotherapy drug in cancer treatment.[3] Some
5-aryl derivatives have also been shown to possess potential antiviral
activity against the human immunodeficiency virus (HIV) and other viral
diseases.[4,5]
There are several ways to synthesize 5-aryl uracils,[5–8] but many of these
routes are restricted to producing only a particular type of 5-aryl uracil. Most
of these methods require the preparation of specific reagents and are not high
in overall yield. One of the most successful methods developed to date is
based on the Suzuki Pd(0)-catalyzed coupling between 2,4-di-t-butoxy-5-
pyrimidineboronic acid and an appropriate aryl bromide (Scheme 1).[9] Unfor-
tunately, this coupling route is low in yield and involves the tedious synthesis
Received in the USA May 9, 2007
Address correspondence to M. Mahmun Hossain, Department of Chemistry and
Biochemistry, University of Wisconsin—Milwaukee, Milwaukee, WI 53201, USA.
E-mail: mahmun@uwm.edu
4173

4174
M. M. Morshed et al.
Figure 1. Cytidine analogs.
of boronic acid. Therefore, there is a need to develop an efficient synthetic
route for uracils.
Our group has already developed an efficient method for the synthesis of
ethyl 3-hydroxy-2-arylpropenate, 1, from the corresponding benzaldehydes,
ethyl diazo acetate (EDA), and the catalyst [(h5-C5H5)(CO)2Fe(THF)]þ
[BF4]2, 2, and/or HBF4.[10] This method can be further extended to the
direct synthesis of 5-aryl uracils (Scheme 2), which is essentially the conden-
sation of urea (3) with the ester 1.
To test the feasibility of this new approach, various reaction conditions
were explored, and it was found that directly heating the ethyl 3-hydroxy-2-
phenylpropenate (1a) and urea in the absence of solvent for 2 h at 130 to
1508C provided the uracil 4a in small amounts (see Scheme 3). The resulting
reaction mixture mostly contained Z- and E-amido esters, 6 and 7, with a
total yield of about 60%. The amido esters were separated by column chrom-
1
atography and were fully characterized by H NMR,13C NMR, and high-
resolution mass spectroscopy.
Scheme 1.
Scheme 2.

Convenient Synthesis of 5-Aryl Uracils
4175
Scheme 3.
The stereochemistry of the intermediates was confirmed using NOE
spectra (Fig. 2). The nuclear overhauser effect (NOE) of the Z-isomer
(a) shows the correlation of the H3 (7.60 ppm) with the ortho-aromatic
proton (7.32 ppm), when there is no correlation between N-H proton
(10.04 ppm) and the ortho-aromatic proton. On the other hand, the NOE
of the E-isomer (b) shows no correlation between H3 (8.28 ppm) and ortho-
aromatic proton (7.24 ppm), when there is correlation between N-H proton
(7.88 ppm) and the ortho-aromatic proton.
Although the product mixture contained a small amount of uracil, it could
not be made into a major product with prolonged heating or at elevated temp-
eratures. At temperatures greater than 1708C, some unidentified by-products
were found. Attempts were then made to convert isolated 6 and 7 to 4a.
The cyclization of amido ester 6 could be initiated easily by dissolving it in
ethanol with 1 equiv. of sodium and refluxing for 1–2 h. After simple
workup using dilute HCI (aq), 4a was obtained in almost quantitative yield.
The isolated amido ester 7 was also converted quantitatively to 4a using the
same procedure. Consequently, the synthesis of uracil (4a) was performed in
one pot by heating the propenate (1a) and urea followed by cyclization with
sodium in ethanol. In addition, to improve the yield of uracil, the esters and
urea were heated in a sealed or closed flask under vacuum.
During heating at 1308C under nitrogen, urea was found to partially
sublime and affect the yield of the intermediate.
The base-catalyzed amonolysis of Z-amido ester 6 to form 4a is a straight-
forward reaction. Although the mechanistic details of conversion of E-amido
ester 7 to uracil 4a were not studied, we propose a plausible mechanism

4176
M. M. Morshed et al.
Figure 2. NOE for the Z- and E-isomer of the intermediate.
Scheme 4.

Convenient Synthesis of 5-Aryl Uracils
4177
outlined in Scheme 4. First, we believe the base deprotonates 7 to form an
enolate 8, which undergoes rotation about C2–C3 carbon bond to form the
enolate 9. Later, the enolate 9 is protonated by ethanol to form Z-amido
ester 6, which cyclizes to form the uracil 4a.
The general scope of the reaction was investigated using substituted ethyl
3-hydroxy-2-arylpropenates, which were prepared according to the method
developed by our group.[10–13] The various esters were successfully treated
with urea, giving the desired uracil products in excellent isolated yield.
Results are summarized in Table 1.
In conclusion, a high-yielding, convenient, and general method has been
developed for the synthesis of 5-aryl uracil. Currently, we are using this
method in the preparation of biologically important uracil compounds.
EXPERIMENTAL SECTION
General Procedure
One equivalent of ethyl-3-hydroxy-2-arylpropenate was mixed with 2 to 3
equiv. of urea in a glass tube. The tube was sealed under vacuum and
heated in a silicon oil bath overnight at 1308C. After cooling, the yellow
solid was dissolved in EtOH (50–100 mL) in a round-bottomed flask, and
2–3 equiv. of sodium were added. After refluxing the reaction mixture at
808C for 4 to 5 h, dilute HCl was added to bring the pH of the solution to 5
to 6, and a white precipitate of 5-aryl uracil was formed. The compound
was collected by filtration and dried in a drying pistol using P2O5 as the
drying agent.
Synthesis of 5-Phenyl Uracil (4a)[14]
Using the general procedure, 5-phenyl uracil (4a) was isolated in 95% yield
from 0.51 g (2.65 mmol) of ethyl-3-hydroxy-2-phenylpropenate (1a) and
0.24 g (4.0 mmol) of urea. The uracil 4a was identified by comparing its
spectra to the reported literature values.[13] 1H NMR (DMSO, 300 MHz) d:
11.23 (s, 1H, NH), 11.12 (s, 1H, broad, NH), 7.58 (d, J ¼ 5.8 Hz, 1H, CH),
7.50 (d, J ¼ 7.1 Hz, 2H, Ph), 7.34 (t, J ¼ 6.9, 2H, Ph), 7.26 (t, J ¼ 7.1 Hz,
1H, Ph).
Synthesis of 5-(2,4-Dimethoxyphenyl) Uracil (4b)
Using the general procedure, 5-(2,4-dimethoxyphenyl) uracil (4b) was isolated in
98% yield from 0.43 g (1.71 mmol) of ethyl-3-hydroxy-2-(2,4-dimethoxyphenyl)
propenate (1b)[13] and 0.11 g (1.83 mmol) of urea. 1H NMR (DMSO, 300 MHz)
d: 11.06 (s, 1H, NH), 10.88 (d, J ¼ 4.9 Hz, 1H, NH), 7.29 (d, J ¼ 5.9 Hz, 1H,

4178
M. M. Morshed et al.
Table l. Isolated yield of 5-aryl uracils
2-Aryl-3-hydroxy-prope-
noic acid ester
Uracil
yield (%)
Entry
1
Uracil
95
2
3
4
98
85
96
5
6
96
97
CH), 7.10 (d, J ¼ 8.3 Hz, 1H, Ph), 6.57 (s, 1H, Ph), 6.51 (d, J ¼ 8.4 Hz, 1H, Ph),
3.77 (s, CH3), 3.71 (s, CH3); 13C NMR (DMSO, 75.4 MHz) d: 163.5, 160.5,
158.5, 151.5, 140.4, 132.2, 114.8, 110.0, 104.9, 98.9, 55.9, 55.6. HRMS (m/z):
calculated for C12H12N2O4, 248.0797; found 248.0803.

Convenient Synthesis of 5-Aryl Uracils
4179
Synthesis of 5-(2-Nitrophenyl) Uracil (4c)
Using the general procedure, 5-(2-nitrophenyl) uracil (4c) was isolated in 85%
yield from 0.39 g (1.64 mmol) of ethyl-3-hydroxy-2-(2-nitrophenyl) propenate
(1c)[13] and 0.28 g (4.67 mmol) of urea. 1H NMR (DMSO, 300 MHz) d: 11.34
(s, 1H, NH), 10.32 (s, 1H, NH), 7.97 (d, J ¼ 8.1 Hz, 1H), 7.73 (m, 2H, Ph), 7.50
(d, J ¼ 7.6 Hz, 1H), 6.59 (t, J ¼ 7.7 Hz, 1H, Ph). 13C NMR (DMSO,
75.4 MHz) d: 162.7, 151.4, 149.2, 140.2, 133.8, 132.5, 129.3, 128.0, 124.5,
111.6. HRMS (m/z): calculated for C10H7N3O4, 233.0437; found 233.0437.
Synthesis of 5-(2-Nitro-5-methoxyphenyl) Uracil (4d)
Using the general procedure, 5-(2-nitro-5-methoxyphenyl) uracil (4d) was
isolated in 96% yield from 0.34 g (1.27 mmol) of ethyl-3-hydroxy-2-(2-
nitro-5-methoxyphenyl) propenate (1d)[13] and 0.23 g (3.83 mmol) of urea.
1H NMR (DMSO, 300 MHz) d: 11.31 (s, 1H, NH), 11.25 (d, J ¼ 6.04, 1H,
NH), 8.01 (d, J ¼ 9.15 Hz, 1H), 7.72 (d, J ¼ 6.04 Hz, 1H), 7.08
(d, J ¼ 2.74 Hz, 1H), 7.00 (d, J ¼ 2.74 Hz, 1H), 3.88 (s, 3H). 13C NMR
(DMSO, 75.4 MHz) d: 162.99, 162.57, 151.46, 142.34, 139.92, 127.06,
117.45, 113.99, 112.19, 56.53. Anal. calculated for C13H15O6N3: C, 50.20;
N, 15.96, H, 3.45. Found: C, 50.20, N, 14.86; H, 3.66.
Synthesis of 5-(4-Methoxyphenyl) Uracil (4e)[14]
Using the general procedure, 5-(4-methoxyphenyl) uracil (4e)[14] was isolated
in 96% yield from 0.33 g (1.486 mmol) of ethyl-3-hydroxy-2-(4-methoxy-
phenyl) propenate (1e)[10] and 0.27 g (4.5 mmol) of urea. The uracil 4e was
identified by comparing its spectra to the reported literature values.[14] 1
H
NMR (DMSO, 300 MHz) d: 11.34 (s, 1H, NH), 11.10 (s, 1H, NH), 7.58
(s, 1H), 7.46 (d, J ¼ 8.75 Hz, 2H), 6.92 (d, J ¼ 8.75, 2H), 3.75 (s, 3H).
Synthesis of 5-(2-Methylphenyl) Uracil (4f)
Using the general procedure, 5-(2-methylphenyl) uracil (4f) was isolated in
97% yield from 0.63 g (3.06 mmol) of ethyl-3-hydroxy-2-(2-methylphenyl)
propenate (1f)[11] and 0.55 g (9.18 mmol) of urea. 1H NMR (DMSO,
300 MHz) d: 11.50 (s, 1H, NH), 11.00 (d, J ¼ 4.57, 1H, NH), 7.36
(d, J ¼ 5.85 Hz, 1H), 7.24–7.06 (m, 4H), 2.15 (s, 3H). 13C NMR (DMSO,
75.4 MHz) d: 163.29, 151.70, 140.57, 137.80, 130.99, 129.98, 128.07,
125.83, 113.70, 20.03. HRMS (m/z): calculated for C10H7N3O4, 202.0742;
found 202.0736.

4180
M. M. Morshed et al.
Synthesis of 6 and 7
A sample of ethyl 3-hydroxy-2-phenylpropenate 1a (0.380 g, 1.97 mmol)
was mixed with urea (0.145 g, 2.41 mmol) and heated at 1308C overnight;
the crude products were separated using a silica column. The 40% Z-inter-
mediate (6), 20% E-intermediate (7), and a small amount of 5-phenyl uracil
(4a) were isolated by column chromatography using pentane/ethyl acetate
solvent.
Z-Intermediate (6)
1H NMR (DMSO, 300 MHz) d: 9.98 (d, J ¼ 11.9 Hz, 1H, NH), 6.70
(d, J ¼ 11.9 Hz, 1H, CH), 7.32 (m, 5H, Ph), 7.04 (s, broad, NH2), 4.18
(q, J ¼ 7.1 Hz, 2H, CH2), 1.18 (t, J ¼ 7.1 Hz, 3H, CH3). 13C NMR (DMSO,
75.4 MHz) d: 167.8 (COOEt), 154.5 (CO), 141.0 (CH), 137.7 (C, Ph), 129.5
(2 CH, Ph), 128.3 (2 CH, Ph), 126.6 (CH, Ph), 105.7 (Ca), 60.2 (OCH2),
14.5 (CH3). HRMS (m/z): calculated for C12H14N2O3, 234.1004. Found
234.1018.
E-Intermediate (7)
1H NMR (DMSO, 300 MHz) d: 8.30 (d, J ¼ 12.7 Hz, 1H, NH), 8.10
(d, J ¼ 12.4 Hz, 1H, CH), 7.35 (m, 3H, Ph), 7.19 (d, J ¼ 7.3 Hz, 2H, Ph), 6.58
(s, broad, NH2), 4.08 (q, J ¼ 7.1 Hz, 2H, CH2), 1.18 (t, J ¼ 7.1 Hz, 3H, CH3).
13C NMR (DMSO, 75.4 MHz) d: 167.3, 154.4, 136.8, 134.1, 130.6, 129.5,
128.8, 128.3, 127.5, 107.7, 60.1, 14.7. HRMS (m/z): calculated for
C12H14N2O3, 234.1004. Found 234.1017.
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