A novel approach for the solid-phase organic synthesis of 1,3-disubstituted uracils

Article abstract of DOI:10.1002/jccs.201000044

A novel procedure for solid-phase organic synthesis of 1,3-disubstituted uracils using a cyclizationcleavage strategy from Wang-acrylate resin, amines and isocyanates. An acrylate ester resin is reacted in turn with PhSeBr and primary amines in one-pot to afford N-substituted α-phenylseleno-β- aminoesters followed by treatment with isocyanates to form α-phenylseleno- β-ureidoester resin. Following oxidation-elimination with excess of 30% hydrogen peroxide and intramolecular cyclization cleavage of the Wang resin using potassium ethoxide as a base to furnish 1,3-disubstituted uracils in good yields (80-86%) and high purities (92-96%).

Full text of DOI:10.1002/jccs.201000044

300
Journal of the Chinese Chemical Society, 2010, 57, 300-304
Communication
A Novel Approach for the Solid-Phase Organic Synthesis of
1,3-Disubstituted Uracils
Mei-Hong Wei (
), Shu-Ying Lin (
), Sheng-Ri Sheng* (
),
Qing Wang (
) and Ming-Zhong Cai (
College of Chemistry and Chemical Engineering, Jiangxi Normal University,
)
Nanchang 330027, P. R. China
A novel procedure for solid-phase organic synthesis of 1,3-disubstituted uracils using a cyclization-
cleavage strategy from Wang-acrylate resin, amines and isocyanates. An acrylate ester resin is reacted in
turn with PhSeBr and primary amines in one-pot to afford N-substituted a-phenylseleno-b-aminoesters
followed by treatment with isocyanates to form a-phenylseleno-b-ureidoester resin. Following oxida-
tion-elimination with excess of 30% hydrogen peroxide and intramolecular cyclization cleavage of the
Wang resin using potassium ethoxide as a base to furnish 1,3-disubstituted uracils in good yields
(80-86%) and high purities (92-96%).
Keywords: Uracil; Solid-phase organic synthesis; Wang-acrylate resin; Intramolecular
cyclization; Cleavage.
INTRODUCTION
RESULTS AND DISCUSSIONS
Combinatorial chemistry is now being increasingly
applied in the facile preparation of chemical libraries for
the discovery of novel biologically active compounds.1
Heterocycles are important elements in many pharmaco-
logically active compounds. Solid-phase organic synthesis
(SPOS) is a powerful technique for the high-speed synthe-
sis of heterocycles.2 The pyrimidinedione ring system is
particularly attractive since it is known to be a core struc-
tural element of some discovered fungicides3 and herbi-
cides.4 Among the heterocycles containing pyrimidine-
dione moiety, uracils have been widely used as bioactive
compounds such as 5-iodouridine,5a (S)-willardiine,5b zi-
dovudine,5c and tifluridine.6 It is therefore out of question
that these compounds have been both widely studied and
used, specially have received attention in combinatorial
synthesis and several SPOS methods for their preparations
have been reported.7 Although SPOS of uracils and their
derivatives are well documented, efforts are continuing for
the development of more efficient methods with experi-
mental simplicity. In connection with our interest in SPOS
of heterocyclic compounds based on polymeric reagents,8
we wish here to report another convenient and efficient
SPOS method for 1,3-disubstituted uracils (Scheme I).
As outlined in Scheme I, treatment of Wang resin 1
loaded with 0.96 mmol/g with 5 equiv of acryloyl chloride
in the presence of N,N-diisopropylethylamine (DIPEA) af-
forded acrylate resin 2 almost in quantitative yield. The
Wang-acrylate resin 2 was characterized by single-bead
microscopy FT-IR,9 which showed complete disappear-
ance of the hydroxyl OH stretch and the appearance of a
C=O stretch at 1724 cm-1 and a C=C stretch at 1651 cm-1.
The resin-bound acrylate 2 was then smoothly reacted with
2.0 equivalents of benzeneselenenyl bromide in DMF at
room temperature to afford resin-bound 3-bromo-2-seleno-
ester intermediate, which was further treated with primary
amine at 50 °C in the presence of in the presence of N,N-
diisopropylethylamine (DIPEA) in one-pot to furnish the
corresponding yellow N-substituted a-phenylseleno-b-
aminoester resins 3, which were monitored by their FT-IR
spectra featuring the ester carbonyl absorptions at 1728-
1733 cm-1 and a moderate strong N-H stretch between
3280-3350 cm-1, with the complete disappearance the band
at 1651 cm-1, corresponding to the C=C olefin absorption
of the resin 2. Additionally, no bromine was found by mi-
croanalysis of resin 3, indicating the conversion of the resin
2 to the resin 3 was complete. It should be noted that, in the
* Corresponding author. E-mail: shengsr@jxnu.edu.cn

Solid-Phase Organic Synthesis of 1,3-Disubstituted Uracils
J. Chin. Chem. Soc., Vol. 57, No. 3A, 2010 301
Scheme I Solid-phase synthetic route to 1,3-disubstituted uracils
Table 1. The yields and purities of 1,3-disubstituted uracils (6a-
6k)
case of a-branched amine (Entries 9 and 10, Table 1) re-
quired longer reaction time or higher temperature to drive
the reaction to completion than those unhindered alkyl
amines.
Yield Purity
Entry
R1
R2
Product
(%)a
(%)b
1
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
n-C4H9
n-C4H9
n-C3H7
n-C3H7
i-C3H7
C6H5
6a
6b
6c
6d
6e
6f
82
85
83
82
86
83
81
85
82
83
80
93
94
93
95
93
92
92
96
93
95
90
Progress of the reaction of resin 3 with an isocyanate
was monitored by the isatin test.10 The reactions were gen-
erally complete in 4 h using a two-fold excess of isocyanate
in CH2Cl2. FT-IR spectra of the a-phenylseleno-b-ureido-
ester resin 4 revealed the presence of the carbonyl stretch at
1728-1733 cm-1 for the ester group and a new strong car-
bonyl absorption at 1655-1672 cm-1, corresponding to the
amide carbonyl group, as well as a broad N-H stretch be-
tween 3300-3400 cm-1.
2
4-MeOC6H4
4-ClC6H4
n-C4H9
C6H5
n-C4H9
C6H5
n-C4H9
C6H5
n-C4H9
3
4
5
6
7
6g
6h
6i
8
9
10
11
i-C3H7
CH2=CHCH2 n-C4H9
6j
6k
It is well known that phenylseleno group is readily
converted to a leaving group giving access to carbon-car-
bon double bond via oxidation followed by b-elimination
under extremely mild conditions.11 As expected, treatment
of the resin 4 with 30% hydrogen peroxide at 0 °C and then
at room temperature afforded the corresponding b-ureido
acrylate ester of Wang’s resin 5, which was found to have
lost all its selenium by elemental analysis indicating the ox-
idation-elimination was complete. After accomplishment
of the oxidation-elimination reaction, the intramolecular
cyclization and cleavage of resin-bound 5, the key for the
success of this protocol was investigated. When NaH was
used in DMF as the previously described method at 0 °C for
30 min,7b and at room temperature in our experiments, or at
reaction temperature of 60-70 °C for 1 h or even for longer
time, the reaction was not complete as monitored by FT-IR
study of the residual resin, which still exhibited carbonyl
a Overall yields based on the loading of Wang’s resin.
b Determined by HPLC of crude cleavage product.
absorptions. Treatment with K2CO3 in DMF gave a better
yield of product 6. However, successful intramolecular
cyclization and cleavage of resin 5 was accomplished by
treatment with KOEt (0.1 M) in EtOH overnight at 60 °C to
afford 1,3-disubstituted uracils 6a-6k containing a variety
of R1 (alkyl, allyl or benzyl) and R2 (alkyl or aryl) substi-
tuent groups in good yields (80-86%) and high purities
(92-96%), as shown in Table 1.
In summary, we have developed a novel, convenient
and effective approach for the SPOS of 1,3-disubstituted
uracils based on Wang resin-bound acrylate, primary
amines and isocyanates. These uracil derivatives were pre-
pared in five steps providing good overall yields and excel-

302 J. Chin. Chem. Soc., Vol. 57, No. 3A, 2010
Wei et al.
lent purities. The simple work-up procedure is suitable for
application to the automated synthesis of diverse uracil-
based compounds.
room temperature, washing thoroughly successively with
CH2Cl2, MeOH, CH2Cl2 and Et2O (2 ´ 5 mL of each) to af-
ford the a-phenylseleno-b-ureidoester resin 4. The washed
resin 4 was then suspended in THF (10 mL), and 30% hy-
drogen peroxide (0.5 mL, 5.8 mmol) was added; the mix-
ture was stirred for 30 min at 0 °C, followed by 1 h at room
temperature. After completion of the reaction, the resin 5
was then filtered and washed successively with THF/H2O
(1:1), THF, MeOH and Et2O (2 ´ 5 mL of each). Then the
resin 5 was cleaved in a solution of KOEt (0.1 mol/L) in
EtOH (30 mL) at 60 °C overnight. After cooling, the resin
was filtered and washed with THF/H2O (1/1) (3 ´ 10 mL),
EtOH (3 ´ 5 mL) and Et2O (3 ´ 5 mL). Evaporation of the
solvent from the filtrate afforded crude products 6a-6k
with 92-96% purity determined by HPLC, which were fur-
ther purified by passing the crude product through silica gel
chromatographic column (ethyl acetate-hexane as the
eluent, 1:3) affording the pure products for their structure
analyses.
EXPERIMENTAL SECTION
General Procedure
Melting points were determined on X4 melting point
1
apparatus and are uncorrected. H NMR (400 MHz) and
13C NMR (100 MHz) spectra were recorded on a Bruker
Avance (400 MHz) spectrometer using CDCl3 as the sol-
vent and TMS as an internal standard. FT-IR spectra were
taken on a Perkin-Elmer SP One FT-IR spectrophotometer.
Microanalyses were performed with a Carlo Erba 1106 ele-
mental analyzer. HPLC analysis was performed on Agilent
1100 automated system having a PDA detector using a gra-
dient with CH3CN/H2O (1 mL/min) on a RP-18e column
(150 ´ 4.6 mm). Wang resin (0.96 mmol/g) and other start-
ing materials were purchased from commercial suppliers
and used without further purification. 1,2-Dichloroethane
was refluxed with phosphorus pentoxide and distilled.
N,N-Dimethylformamide (DMF) was refluxed with cal-
cium hydride and distilled under reduced pressure, then
dried over molecular sieves 4 Å prior to use.
1-Benzyl-3-phenylpyrimidine-2,4-dione (6a)
1
White solid, mp 152-154 °C (lit.12 153-155); H
NMR: d = 7.50-7.33 (m, 8 H), 7.26-7.22 (m, 3 H), 5.85 (d, J
= 7.9 Hz, 1 H), 4.94 (s, 2 H); 13C NMR: d = 163.0, 151.7,
142.3, 135.0, 134.8, 129.2, 129.0, 128.8, 128.5, 128.3,
128.1, 102.3, 52.5; IR (KBr): n = 3060, 2925, 1715, 1660,
1445, 1385, 1226, 698 cm-1; Anal. Calcd for C17H14N2O2:
C, 73.37; H, 5.07; N, 10.07. Found: C, 73.43; H, 5.16; N,
10.11.
Preparation of Wang-acrylate resin 2
Wang resin (1.0 g, 0.96 mmol/g) was swollen in
CH2Cl2 (10 mL), DIPEA (0.65 g, 5.0 mmol) and acryloyl
chloride (0.45 g, 5.0 mmol) were added and the reaction
mixture was shaken at room temperature for 4 h. After
which, the mixture was filtered and the resin washed se-
quentially with DMF, H2O, MeOH, CH2Cl2, and Et2O (2 ´
10 mL of each) and dried overnight in a vacuum oven at 40
°C to afford resin 2. IR (KBr): n = 3060, 3025, 2922, 1724,
1651, 1585, 1569, 1495, 1454, 1351, 1250, 1144, 1106,
950, 840 cm-1.
1-Benzyl-3-(4-methoxyphenyl)pyrimidine-2,4-dione
(6b)
White solid, mp 158-160 °C (lit.7c 158-160 °C); 1H
NMR: d = 7.38-7.25 (m, 6 H), 7.16 (d, J = 8.8 Hz, 2 H),
7.01 (d, J = 8.8 Hz, 2 H), 5.81 (d, J = 7.9 Hz, 1 H), 4.91 (s, 2
H), 2.84 (s, 3 H); 13C NMR: d = 163.0, 159.3, 151.8, 142.3,
135.2, 129.2, 129.0, 128.6, 128.2, 127.5, 114.5, 102.2,
55.1, 52.1; IR (KBr): n = 3062, 1712, 1661, 1510, 1390,
1445, 1248, 825 cm-1; Anal. Calcd for C18H16N2O3: C,
70.12; H, 5.23; N, 9.09. Found: C, 70.19; H, 5.30; N, 9.17.
1-Benzyl-3-(4-chlorophenyl)pyrimidine-2,4-dione (6c)
White solid, mp 155-157 °C; 1H NMR: d = 7.53 (d, J
= 8.4 Hz, 2 H), 7.40-7.28 (m, 6 H), 7.22 (d, J = 8.4 Hz, 2
H), 5.82 (d, J = 7.8 Hz, 1 H), 4.88 (s, 2 H); 13C NMR: d =
163.8, 151.5, 143.0, 136.2, 132.5, 130.6, 129.2, 129.0,
128.8, 128.3, 102.4, 120.9, 52.6; IR (KBr): n = 3063, 1717,
1665, 1445, 1388, 1350, 1225, 834, 700 cm-1; Anal. Calcd
for C17H13ClN2O2: C, 65.29; H, 4.19; N, 8.96. Found: C,
65.37; H, 4.25; N, 8.99.
General preparation of 1,3-disubstituted uracils 6a-6k
To a suspension of the swollen resin 2 (1.0 g) in anhy-
drous DMF (10 mL) was added PhSeBr (2.0 mmol) added.
After 30 min with shaking at room temperature, primary
amines (5.0 mmol) and DIPEA(5.0 mmol) were added, and
the mixture was allowed to shake at 50 °C for 12 h. After
which, the mixture was filtered and the resin washed se-
quentially with DMF, H2O, THF, MeOH and CH2Cl2 (2 ´
10 mL of each), and dried overnight in a vacuum oven at 40
°C to afford the yellow N-substituted a-phenylseleno-b-
aminoester resin 3, which was swelled in anhydrous CH2Cl2
(10 mL) at room temperature for 30 min followed by addi-
tion of isocyanate (2.0 mmol). After 4 h with shaking at

Solid-Phase Organic Synthesis of 1,3-Disubstituted Uracils
J. Chin. Chem. Soc., Vol. 57, No. 3A, 2010 303
1-Benzyl-3-butylpyrimidine-2,4-dione (6d)
62.83; H, 8.63; N, 13.32. Found: C, 62.94; H, 8.75; N,
13.39.
Colorless oil (lit.7c oil); 1H NMR: d = 7.40-7.27 (m, 5
H), 7.15 (d, J = 7.8 Hz, 1 H), 5.70 (d, J = 7.8 Hz, 1 H), 4.91
(s, 2 H), 3.95 (t, J = 7.6 Hz, 2 H), 1.62-1.60 (m, 2 H), 1.37-
1.34 (m, 2 H), 0.95 (t, J = 7.5 Hz, 3 H); 13C NMR: d =
162.5, 151.3, 141.5, 135.3, 128.8, 128.2, 127.7, 102.0,
52.1, 41.2, 29.5, 20.2, 13.5; IR (neat): n = 3055, 2966,
1712, 1655, 1455, 1357, 1238, 804 cm-1; Anal. Calcd for
C15H18N2O2: C, 69.74; H, 7.02; N, 10.84. Found: C, 69.82;
H, 7.13; N, 10.72.
1-Phenyl-3-(i-propyl)pyrimidine-2,4-dione (6i)
White solid, mp 130-132 °C; 1H NMR: d = 7.50-7.46
(m, 2 H), 7.38 (d, J = 7.7 Hz, 1 H), 7.24-7.18 (m, 3 H), 5.80
(d, J = 7.7 Hz, 1 H), 3.78-3.76 (m, 1 H), 1.20 (d, J = 6.6 Hz,
6 H); 13C NMR: d = 163.6, 151.6, 142.7, 135.3, 129.42,
128.7, 128.1, 101.2, 44.5, 22.5; IR (KBr): n = 3050, 2965,
1710, 1663, 1446, 1387, 1370, 1245, 695 cm-1; Anal. Calcd
for C13H14N2O2: C, 67.81; H, 6.13; N, 12.17. Found: C,
67.92; H, 6.20; N, 12.14.
1-Butyl-3-phenylpyrimidine-2,4-dione (6e)
White solid, mp 99-101 °C (lit.7c 98-100 °C); H
1-Butyl-3-(i-propyl)pyrimidine-2,4-dione (6j)
Colorless oil; 1H NMR: d = 7.05 (d, J = 7.8 Hz, 1 H),
5.64 (d, J = 7.8 Hz, 1 H), 3.80-3.78 (m, 1 H), 3.73 (t, J = 7.5
Hz, 2 H), 1.71-1.69 (m, 2 H), 1.38-1.35 (m, 2 H), 1.21 (d, J
= 6.6 Hz, 6 H), 0.96 (t, J = 7.6 Hz, 3 H); 13C NMR: d =
163.0, 151.5, 142.3, 101.3, 50.5, 43.9, 30.9, 22.2, 20.0,
13.6; IR (neat): n = 3052, 2964, 1707, 1660, 1455, 1354,
1385, 1370, 1240, 810 cm-1; Anal. Calcd for C11H18N2O2:
C, 62.83; H, 8.63; N, 13.32. Found: C, 62.90; H, 8.73; N,
13.40.
1
NMR: d = 7.50-7.46 (m, 2 H), 7.40 (d, J = 7.6 Hz, 1 H),
7.24-7.20 (m, 3 H), 5.81 (d, J = 7.6 Hz, 1 H), 3.75 (t, J = 7.5
Hz, 2 H), 1.69-1.67 (m, 2 H), 1.37-1.35 (m, 2 H), 0.98 (t, J
= 7.3 Hz, 3 H); 13C NMR: d = 163.0, 151.5, 143.1, 134.9,
129.3, 128.5, 128.1, 101.7, 50.1, 31.2, 19.5, 13.5; IR
(KBr): n = 3056, 2962, 1710, 1660, 1445, 1116, 696 cm-1;
Anal. Calcd for C14H16N2O2: C, 68.83; H, 6.60; N, 11.47.
Found: C, 68.91; H, 6.69; N, 11.50.
1,3-Dibutylpyrimidine-2,4-dione (6f)
Colorless oil (lit.12 oil); 1H NMR: d = 7.10 (d, J = 7.7
Hz, 1 H), 5.69 (d, J = 7.7 Hz, 1 H), 3.95 (t, J = 7.6 Hz, 2 H),
3.73 (t, J = 7.5 Hz, 2 H), 1.68-1.59 (m, 4 H), 1.41-1.34 (m,
4 H), 0.97-0.91 (m, 6 H); 13C NMR: d = 163.2, 151.3,
142.0, 101.4, 49.6, 41.0, 30.9, 29.5, 20.3, 19.8, 13.6, 13.5;
IR (neat): n = 3050, 2960, 2872, 1705, 1655, 1456, 1356,
1225, 805 cm-1; Anal. Calcd for C12H20N2O2: C, 64.26; H,
8.99; N, 12.49. Found: C, 64.33; H, 9.08; N, 12.54.
1-Phenyl-3-propylpyrimidine-2,4-dione (6g)
1-Allyl-3-butylpyrimidine-2,4-dione (6k)
Colorless oil (lit.7c oil); 1H NMR: d = 7.08 (d, J = 7.7
Hz, 1 H), 5.89-5.87 (m, 1 H), 5.74 (d, J = 7.7 Hz, 1 H),
5.34-5.25 (m, 2 H), 4.36 (d, J = 5.5 Hz, 2 H), 3.94 (t, J = 7.6
Hz, 2 H), 1.61-1.59 (m, 2 H), 1.37 (m, 2 H), 0.94 (t, J = 7.5
Hz, 3 H); 13C NMR: d = 163.0, 151.5, 141.5, 131.6, 119.1,
101.9, 51.1, 41.0, 29.5, 20.3, 13.9; IR (neat): n = 3045,
2928, 2856, 1708, 1664, 1455, 1230, 805 cm-1; Anal. Calcd
for C11H16N2O2: C, 63.44; H, 7.74; N, 13.45. Found: C,
63.53; H, 7.85; N, 13.57.
White solid, mp 135-136 °C (lit.7c 134-136 °C); 1H
NMR: d = 7.51-7.46 (m, 2 H), 7.40 (d, J = 7.8 Hz, 1 H),
7.24-7.20 (m, 3 H), 5.81 (d, J = 7.8 Hz, 1 H), 3.71 (t, J = 7.4
ACKNOWLEDGEMENTS
Hz, 2 H), 1.76-1.74 (m, 2 H), 0.95 (t, J = 7.4 Hz, 3 H); 13
C
We gratefully acknowledge financial support from
the Natural Science Foundation of Jiangxi Province of
China (No. 2008GZH0029) and the Research Program of
Jiangxi Province Department of Education (No. GJJ08165).
NMR: d = 163.2, 151.5, 142.9, 135.1, 129.2, 128.6, 128.2,
101.8, 51.4, 22.0, 10.7; IR (KBr): n = 3052, 2967, 1709,
1662, 1445, 1336, 1245, 698 cm-1; Anal. Calcd for
C13H14N2O2: C, 67.81; H, 6.13; N, 12.17. Found: C, 67.90;
H, 6.21; N, 12.12.
Received November 1, 2009.
1-Butyl-3-propylpyrimidine-2,4-dione (6h)
Colorless oil (lit.7c oil); 1H NMR: d = 7.08 (d, J = 7.8
Hz, 1 H), 5.66 (d, J = 7.8 Hz, 1 H), 3.89 (t, J = 7.5 Hz, 2 H),
3.66 (t, J = 7.3 Hz, 2 H), 1.69-1.66 (m, 2 H), 1.58-1.54 (m,
2 H), 1.33-1.30 (m, 2 H), 0.96-0.90 (m, 6 H); 13C NMR: d =
163.2, 151.3, 142.0, 101.5, 51.5, 40.9, 30.1, 22.3, 20.0,
13.8, 10.7; IR (neat): n = 3052, 2964, 1707, 1660, 1455,
1354, 1239, 802 cm-1; Anal. Calcd for C11H18N2O2: C,
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