Synthesis of 5-substituted uracils and 2,4-dimethoxypyrimidines by Wittig olefination

Article abstract of DOI:10.1002/jhet.5570420615

A variety of new 5-alkenyluracils has been prepared in high yields by Wittig olefination of 5-formyl-l-octyluracil, 5-formyl-1,3-dioctyluracil and 5-formyl-2,4-dimethoxy pyrimidine with stabilized and semistabilized phosphorus ylides. The conformation of the products is discussed on the basis of ¹H NMR spectral data.

Full text of DOI:10.1002/jhet.5570420615

Synthesis of 5-Substituted Uracils and 2,4-Dimethoxypyrimidines
by Wittig Olefination
Sep-Oct 2005
1135
*
Evdoxia Coutouli-Argyropoulou and Christina Zachariadou
Laboratory of Organic Chemistry, Department of Chemistry, Aristotle University of Thessaloniki,
Thessaloniki, 54124, Greece
Received February 25, 2005
A variety of new 5-alkenyluracils has been prepared in high yields by Wittig olefination of 5-formyl-1-octy-
luracil, 5-formyl-1,3-dioctyluracil and 5-formyl-2,4-dimethoxy pyrimidine with stabilized and semistabi-
1
lized phosphorus ylides. The conformation of the products is discussed on the basis of H NMR spectral
data.
J. Heterocyclic Chem., 42, 1135 (2005).
Introduction.
Scheme 1. The 1-octyl and 1,3-dioctylthymines 2 and 3
were obtained by alkylation of thymine with sodium
hydride and octyl bromide. By varying the ratio of the
alkylating agent to thymine, mono or disubstituted deriva-
tives are obtained as the main products. For the oxidation
of the methyl group a procedure described in the literature
[7] for analogous derivatives was followed, which after
optimisation of the reaction conditions gave the desired
aldehydes in satisfactory yields (60 – 72 %).
The introduction of substituents at the C-5 position of
uracil is of great practical interest for both purposes of
labelling and synthesis of new biological active com-
pounds. The C-5 pyrimidine position is usually the posi-
tion of choice for labelling since it is not involved in the
Watson-Crick base pairing and furthermore C-5 substi-
tuted pyrimidines are compatible with polymerase
enzymes [1]. On the other hand suitably C-5 substituted
uracils and uridines are included among the most active
and selective antiviral agents [2]. Structure -activity rela-
tionships have shown that the antiviral activity is enhanced
when the C-5 substituent is unsaturated in conjugation
with the pyrimidine ring, has E-stereochemistry and
includes an hydrophobic electronegative function
[2b,2c,2h]. The above structural features resulting in the
enhancement of the electrophilic character of the carbon-6
of the pyrimidine ring are reasonably understood on the
basis of the thymidylate synthetase mechanism [3].
The most already applied method for the introduction of
unsaturated substituents into the 5-position of pyrimidines is
the palladium-catalysed addition of alkenes to either 5-halo-
genated or 5-mercury derivatives [2a,2b,2c,2d,2f,2h,2j,4].
Surprisingly the widely used general and effective Wittig
olefination has been found a rather limited application and
only a few cases are referred to give some satisfactory
results [5].
In connection with our former studies on nucleic bases
modifications [1c,6], we studied in this paper the Wittig reac-
tions of mono and disubstituted formyluracils 5 and 6 and
dimethoxyformylpyrimidine 7. The octyl substituted deriva-
tives 5 and 6 have been chosen for purposes of higher solu-
bility and hydrophobicity, whereas compound 7 is a pro-
tected derivative of 5-formyluracil. As ylides we have cho-
sen the stabilized and semistabilized ylides 8a-d which have
an electronegative hydrophobic function and satisfy one of
the basic structure requirements for antiviral activity.
The ylides 8 were prepared by dehydrohalogenation of
the corresponding phosphonium salts and reacted with the
aldehydes 5, 6, 7 to give the alkene derivatives 9, 10, 11
according to Scheme 2. The reactions with the stabilized
ylides were carried out after the isolation of the ylide in
dichlomethane and methanol solutions. In the reactions
with the semistabilized ylides 8c and 8d the formation of
the ylide was made in situ by potassium tert-butoxide in
benzene or under biphasic conditions in dichloromethane/
Results and Discussion.
The aldehydes 5, 6 and 7 were prepared by oxidation of
the corresponding 5-methylderivatives according to

1136
E. Coutouli-Argyropoulou and C. Zachariadou
Vol. 42
aqueous NaOH solution. In all cases the ylide was used in
excess (1.5:1) and the reactions were carried out at room
temperature and were monitored by TLC until consump-
tion of the aldehyde. The yields of the reaction products
after their isolation by column chromatography were very
satisfactory ranging between 77 – 98 %. The reaction con-
Table
1
Reaction conditions, yields and ratio of the (Z)/(E)- isomers
of the reactions of ylides 8 with aldehydes 5, 6, 7.
Starting
aldehyde
Starting
ylide
Solvent, Reaction time
Product
Yield %
Ratio of Z/E
isomers
5
5
6
6
7
7
5
5
6
6
7
7
5
5
6
6
7
7
6
6
7
7
8a
8a
8a
8a
8a
8a
8b
8b
8b
8b
8b
8b
8c
8c
8c
8c
8c
8c
8d
8d
8d
8d
CH Cl , 6 hours
9a
9a
96
94
88
90
93
95
80
80
81
88
85
79
78
85
88
98
80
90
90
77
80
85
0.8/1
1.4/1
1/1
1/1
0.2/1
2/1
0.2/1
1.1/1
1/1
1/1
2/1
2
2
CH OH, 6 hours
3
CH Cl , 6 hours
10a
10a
11a
11a
9b
2
2
CH OH, 6 hours
3
CH Cl , 6 hours
2
2
CH OH, 6 hours
3
CH Cl , 3 days
2
2
CH OH, 8 hours
9b
3
CH Cl , 3 days
10b
10b
11b
11b
9c
2
2
CH OH, 8 hours
3
CH Cl , 3 days
2
2
CH OH, 8 hours
5/1
3
t-BuOK, C H , 2 hours
2.2/1
1.2/1
11/1
2.6/1
2/1
2/1
4/1
18/1
3/1
4/1
6
6
NaOH/CH Cl , 2 hours
9c
2
2
t-BuOK, C H , 2 hours
10c
10c
11c
11c
10d
10d
11d
11d
6
6
NaOH/CH Cl , 2 hours
2
2
t-BuOK, C H , 2 hours
6
6
NaOH/CH Cl , 2 hours
2
2
t-BuOK, C H , 2 hours
6
6
NaOH/CH Cl , 2 hours
2
2
t-BuOK, C H , 2 hours
6
6
NaOH/CH Cl , 2 hours
2
2

Sep-Oct 2005
Synthesis of 5-Substituted Uracils and 2,4-Dimethoxypyrimidines
1137
ditions, the yields of the products and the ratio of the
(Z)/(E)- isomers are given in Table 1. It should be men-
tioned that in the case of the reaction of the ylide 8d with
the aldehyde 5 it was not possible to isolate any product
although there were indications for the formation of the
10a. These observations are in accordance with a preferred
conformation [A] between the two possible conformations
[A] and [B] for the (Z)-isomers as depicted in Figure 1. In
the less hindered conformation [A] the H-6 undergoes the
1
neighbouring group effect of R substituent, which is
1
1
1
expected alkenes in the H NMR of the crude reaction
mixture.
shielding for R = aromatic and deshielding for R =
CO CH , as it comes out from molecular models.
2
3
As it comes out from Table 1 the semistabilized ylides
8c and 8d showed almost the same reactivity in both the
reaction conditions applied. The stabilized ylide 8a
showed also almost the same reactivity in both methanol
and dichloromethane solutions, whereas reactions with
ylide 8b were faster in methanol solutions. In regard with
the regioselectivity of the reactions no severe regularities
were observed. It is known that Wittig reactions of stabi-
lized ylides with aldehydes lead stereoselectively to the
preferential formation of (E)-alkenes, whereas reactions
with the non-stabilized ylides lead to the formation of the
thermodynamically less favourable (Z)-alkenes and semi-
stabilized ylides with moderate activity afford mixtures of
(Z)-alkenes and (E)-alkenes [8]. Furthermore in the reac-
tions of the stabilized ylides the proportion of (Z)-isomer is
increased in protic solvents [8]. In our case however reac-
tions with the stabilized ylides 8a and 8b gave mixtures of
(Z)- and (E) isomers even in aprotic solvents, whereas an
increase of the ratio of (Z)-isomer was observed in the
reactions with the aldehydes 5 and 7 in methanol. In the
reaction with the semi-stabilized ylides 8c and 8d the for-
mation of (Z)-isomer is favoured in all cases.
Table 2
Chemical shifts of 6-H pyrimidine protons.
Compound δ H-6 of (Z)-isomer δ H-6 of (E)-isomer ∆δ [(Z) - (E)]
1
2
3
4
5
6
7
8
9a
10a
11a
9b
10b
11b
9c
10c
11c
10d
11d
9.27
9.10
8.66
6.90
6.82
7.77
6.97
6.96
7.96
6.95
7.97
7.33
7.37
8.29
7.49
7.50
8.45
7.38
7.37
8,43
7.38
8.42
1.94
1.73
0.37
-0.59
-0.68
-0.68
-0.41
-0.41
-0.47
-0.33
-0.45
9
10
11
Conformation [A] is further supported by NOE mea-
surements carried out on compound (Z)-9a. Thus upon sat-
uration of 6-H both olefinic protons substain positive NOE
effect almost of the same magnitude. The mutual NOE
enhancement of 6-H upon saturation of either olefinic pro-
ton is also positive and of the same magnitude. For confor-
The structure assignment of the obtained alkenes 9, 10
and 11 was based on their elemental analysis and spectral
data. In the mass spectra they give peaks corresponding to
mation [B] the mutual NOE effect between H-6 and H
having an almost linear arrangement with H is expected to
b
a
1
13
be negative.
the molecular ion and in the H NMR and C NMR give
the expected chemical shifts. The distinction between (E)-
and (Z)- isomers was easily made on the basis of the
olefinic protons coupling constant value ranging between
11.6–13.2 Hz for (Z)-isomers and 16.0–16.7 Hz for (E)-
1
isomers. A feature worth mentioning in the H NMR of
the obtained products is the chemical shift of 6-H pyrimi-
dine ring proton, which permits some suggestions about
the preferred conformation of the alkenyl chain in the (Z)-
isomers. The chemical shifts values of 6-H pyrimidine ring
protons of (E)- and (Z)-isomers and their differences are
given in Table 2. Assuming that the variations in the chem-
ical shift of H-6 are governed mainly by the electron with-
1
drawing effect of the R substituent, H-6 is expected to be
The proposed preferred conformation [A] explains to
some degree the observed reduced antiviral reactivity of 5-
[(Z)-alkenyl]-uracils [2b,2c,2h], since in this conformation
the 6-position of uracil is too hindered to be attacked by
the nucleophile cysteine group according to the thymidy-
late synthetase mechanism.
The dimethoxyderivatives 11 are protected forms of
uracils from which the last can be obtained after the
removal of the methyl groups under several conditions [9].
more downfield shifted in the (E)-isomers compared to the
(Z)-isomers since conjugation works more effectively in
the less sterically hindered (E)-isomers. Indeed when R is
aromatic (entries 4 – 11 of Table 2), the H-6 chemical shift
of (E)-isomer is larger than that of (Z)-isomer. On the con-
trary when R is carboxymethyl (entries 1 – 3 of Table 2),
the 6-H of the (Z)-isomer is more shifted than the 6-H of
the (E)-isomer, especially in the uracil derivatives 9a and
1
1

1138
E. Coutouli-Argyropoulou and C. Zachariadou
Vol. 42
reported procedures [8b,11]. 2,4-Dimethoxy-5-methylpyrimidine
4 was prepared as described in the literature [12].
In a representative experiment we have transformed quan-
titatively dimethoxyderivative 11c to uracil derivative 12
by heating in acetic acid with sodium iodide according to
Scheme 3. It was observed that under the applied condi-
tions (Z)- to (E)- isomerization also takes place. Thus,
treatment of a mixture of Z, E-11c gave the (E)-uracil 12.
Preparation of 1-Octylthymine (2) and 1,3-Dioctylthymine (3).
A mixture of thymine (2.46 g, 20 mmoles) and sodium hydride
(0.88 g 60% oil dispersion, 22 mmoles) in dry DMF (30 ml) was
stirred at 80° under argon atmosphere for 1 hour. Then octylbro-
mide (3.45 ml, 20 mmoles) was added and the reaction mixture
was heated at 80° for another 4 hours. After that the reaction mix-
ture was poured into methylene chloride/water and the organic
layer was extracted three times with water to remove the DMF.
After drying with sodium sulfate and evaporation of the solvent
the residue was chromatographed on a silica-gel column with
hexane-ethyl acetate (4:1) as the eluent. From the column they
were obtained in order of elution 0.77 g (11 %) of 3 and 3.10 g
(65 %) of 2. In a repeated procedure using sodium hydride and
octylbromide in 2 equivalence compounds 3 and 2 were isolated
1
in 50 and 20 % yields respectively. The H NMR spectrum of
compound 2 was in agreement with the literature data [13].
1,3-Dioctylthymine (3).
The effectiveness of the applied conditions for the pur-
poses of isomerization was also tested to other than
methoxy derivatives. Thus dioctylderivative Z-10e was
quantitatively transformed to E-10e after heating one hour
in acetic acid in the presence of sodium iodide. It should be
mentioned that prolonged heating in acetic acid without
sodium iodide did not result in any change of the ratio of
the isomers. Alternatively, a mixture E,Z-11a was also
transformed to E-11a by treatment with thiophenol in the
presence of 2,2'-azobis(2-methylpropionitrile) (AIBN)
according to a procedure previously described in the litera-
ture [10]. Thus the lack of the stereoselectivity or the per-
formed Wittig reactions with the predominance of (Z)-iso-
mers in most cases does not reduce their utility for the syn-
thesis of the most promising for biological purposes (E)-
isomers.
1
This compound was obtained as an oil; H nmr: δ 0.87 (m, 6H,
CH ), 1.26-1.30 (m, 20H, CH CH (CH ) CH ), 1.64 (m, 4H,
3
2
2
2 5
3
CH CH (CH ) CH ), 1.92 (s, 3H, CH ), 3.69 (t, J = 7.4 Hz, 2H,
CH CH (CH ) CH ), 3.93 (t, J = 7.4 Hz, 2H, CH CH (CH ) CH ),
2
2
2 5
3
3
2
2
2 5
3
2
2
2 5
3
13
6.95 (s, 1H, 6-H); C nmr: δ 13.0 and 14.0 (CH ), 22.5, 26.4, 26.6,
3
27.5, 29.0, 29.2, 31.6 and 31.7 (CH (CH ) CH ), 41.4 and 49.4
2
2 6
3
(CH (CH ) CH ), 109.5 (C-5), 138.2 (C-6), 151.3 (C-2), 163.7
2
2 6
3
+
(C-4); ms: m/z 350 (M , 25% rel. int.).
Anal. Calcd. for C N O : C, 71.95; H, 10.93; N, 7.99.
H
21 38
2 2
Found: C, 71.57; H, 11.23; N, 7.80.
General Procedure for the Oxidation of Methyl Derivatives (2, 3, 4).
A solution of the methyl pyrimidine (10 mmoles) and 2,6-luti-
dine (4.1 ml, 35 mmoles) in acetonitrile (40 ml) was added to a
solution of K S O (5.4 g, 20 mmoles) and CuSO .5H SO (1g,
2
2
8
4
2
4
4 mmoles) in water (40 ml). The reaction mixture was heated in
an oil bath at 80° and the reaction mixture was monitored by
TLC. After 1 hour TLC showed only traces of the starting methyl
derivative and the heating was stopped. Applying longer reaction
times at the same temperature or at lower temperatures side prod-
ucts were formed lowering the yield of the reaction. After cooling
the reaction mixture was concentrated to half the initial volume
and the remaining solution was extracted with ethyl acetate. The
organic layer was successively washed with water then aqueous 5
% EDTA. The combined water layers were extracted with chloro-
form then the organic layers were combined, dried over sodium
sulfate and concentrated. The residue was chromatographed on a
silica gel column with hexane-ethyl acetate (4:1 for 5, 8:1 for 6
2:1 for 7) as the eluent. Compounds 5, 6 and 7 were obtained in
71 %, 60 % and 72 % yields respectively. The dimethoxy deriva-
tive 7 showed the same spectral characteristics with those given
in the literature [14].
In conclusion, Wittig olefination has been proved to be a
very simple, effective and convenient procedure for the
synthesis of a variety of 5-substituted uracils in high yields
avoiding expensive and toxic metal catalysed procedures.
EXPERIMENTAL
Mp’s are uncorrected and were determined on a Kofler hot-
1
stage microscope. H nmr spectra were recorded at 300 MHz on
13
a Bruker 300 AM spectrometer and C nmr spectra at 75.5 MHz
on the same spectrometer and are quoted relative to tetramethyl-
silane as internal reference, in deuteriochloroform solutions,
unless otherwise stated. Values of J are given in Hz. Mass spectra
were performed on a VG-250 spectrometer with ionization
energy maintained at 70 eV. Microanalyses were performed on a
Perkin-Elmer 2400-II element analyser. Column chromatography
was carried out on Merck Kieselgel (particle size 0.063-0.200
mm) and solvents were distilled before use. The ylides 8a and 8b,
4-nitrobenzylltriphenylphosphonium chloride and 4-pyridinyl-
methyltriphenylphosphonium chloride, precursors of the ylides
8c and 8d respectively, were prepared according to previously
5-Formyl-1-octyluracil (5).
This compound was obtained as a white solid mp 108-110°;
1
H nmr: δ 0.81 (t, J = 6.4 Hz, 3H, CH ), 1.23 (m, 10H,
3
CH CH (CH ) CH ), 1.64 (m, 2H, CH CH (CH ) CH ), 3.77
2
2
2 5
3
2
2
2 5
3
(t, J = 7.6 Hz, 2H, CH CH (CH ) CH ), 8.03 (s, 1H, 6-H),
2
2
2 5
3
13
9.14 (s, 1H, NH), 9.95 (s, 1H, CHO); C nmr: δ 14.0 (CH ),
3
22.3, 26.3, 29.0, 29.1 and 31.7 (CH (CH ) CH ), 50.2
2
2 6
3

Sep-Oct 2005
Synthesis of 5-Substituted Uracils and 2,4-Dimethoxypyrimidines
1139
(CH (CH ) CH ), 110.9 (C-5), 149.2 (C-6), 149.7 (C-2), 162.1
OCH ), 3.74 (t, J = 7.2 Hz, 2H, CH CH (CH ) CH ), 6.93 (d, J =
3 2 2 2 5 3
2
2 6
3
+
(C-4), 186.1 (CHO); ms: m/z 252 (M , 22% rel. int.).
Anal. Calcd. for C N O : C, 61.88; H, 7.99; N, 11.10.
16.2 Hz, 1H, CH=CH), 7.22 (d, J = 16.2 Hz, 1H, CH=CH), 7.33
13
H
(s, 1H, 6-H), 8.99 (br s, 1H, NH); C nmr: δ 14.0 (CH ), 22.6,
13 20
2
3
3
26.3, 26.4, 29.1, 29.7 and 31.7 (CH (CH ) CH ), 49.4
Found: C, 61.57; H, 8.02; N, 11.20.
2
2 6
3
(CH (CH ) CH ), 51.6 (COOCH ), 109.8 (C-5), 119.3 and 135.9
2
2 6
3
3
5-Formyl-1,3-dioctyluracil (6).
(CH=CH), 146.3 (C-6), 149.5 (C-2), 161.4 (C-4), 167.9
1
+
This compound was obtained as a white solid mp 49-51°; H
nmr: 0.79 (m, 6H, CH ), 1.19-1.24 (m, 20H,
CH CH (CH ) CH ), 1.56-1.96 (m, 4H, CH CH (CH ) CH ),
(COOCH ); ms: m/z 308 (M , 17% rel. int.).
3
δ
Anal. Calcd. for C
H N O : C, 62.32; H, 7.84; N, 9.08.
3
16 24 2 4
Found: C, 62.28; H, 7.81; N, 8.90.
2
2
2 5
3
2
2
2 5
3
3.80 (t, J = 7.3 Hz, 2H, CH CH (CH ) CH ), 3.87 (t, J = 6.1 Hz,
2
2
2 5
3
5-[(Z)-3-Methoxy-3-oxo-1propenyl]-1-octyluracil (Z-9a).
2H, CH CH (CH ) CH ), 8.04 (s, 1H, 6-H), 9.94 (s, 1H, CHO);
2
2
2 5
3
13
1
C nmr: δ 14.1 (CH ), 22.6, 26.4, 26.9, 27.5, 29.0, 29.2, 31.7
and 31.8 (CH (CH ) CH ), 41.6 and 51.0 (CH (CH ) CH ),
This compound was obtained as a white solid mp 110-112°; H
3
nmr: δ 0.87 (t, J = 6.6 Hz, 3H, CH ), 1.30 (m, 10H,
2
2 6
3
2
2 6
3
3
110.3 (C-5), 146.9 (C-6), 150.4 (C-2), 161.8 (C-4), 187.1 (CHO);
CH CH (CH ) CH ), 1.75 (m, 2H, CH CH (CH ) CH ), 3.73
2 2 2 5 3 2 2 2 5 3
+
ms: m/z 364 (M , 23% rel. int.).
(s, 3H, OCH ), 3.82 (t, J = 7.2 Hz, 2H, CH CH (CH ) CH ),
3 2 2 2 5 3
Anal. Calcd. for C
C, 69.12; H, 9.85; N, 7.86.
H
N O : C, 69.19; H, 9.95; N, 7.68. Found:
5.91 (d, J = 13.2 Hz, 1H, CH=CH), 7.02 (d, J = 13.2 Hz, 1H,
21 36
2 3
13
CH=CH), 9.27 (s, 1H, 6-H), 9.58 (br s, 1H, NH); C nmr: δ 14.1
(CH ), 22.6, 26.4, 29.1, 29.7 and 31.8 (CH (CH ) CH ), 49.6
3
2
2 6
3
General Procedure for the Wittig Reaction of Aldehydes 5, 6 and
7 with the Stabilized Ylides 8a and 8b.
(CH (CH ) CH ), 51.6 (COOCH ), 108.3 (C-5), 116.9 and 134.6
2
2 6
3
3
(CH=CH), 148.5 (C-6), 150.1 (C-2), 163.1 (C-4), 167.3
+
A mixture of the aldehyde (1 mmole) and the ylide (1.5
mmoles) in dry methylene chloride (10 ml) or dry methanol (10
ml) was stirred at room temperature until the aldehyde was con-
sumed, as indicated by TLC. The solvent was then evaporated
and the residue was chromatographed on a silica gel column with
hexane-ethyl acetate (2:1 for the reactions of 5, 5:1 the for reac-
tions of 6, 3:1 for the reactions of 7) as the eluent. With the
exceptions of E,Z-10a which was obtained as a mixture and Z-9b
which was obtained only as a mixture with the (E)-isomer, in the
other cases it was possible to isolate from the column fractions
with separated pure (E)- and (Z)-isomers.
(COOCH ); ms: m/z 308 (M , 38% rel. int.).
3
Anal. Calcd. for C
H N O : C, 62.32; H, 7.84; N, 9.08.
16 24 2 4
Found: C, 62.15; H, 7.58; N, 8.89.
5-[(E,Z)-3-Methoxy-3-oxo-1propenyl]-1,3-dioctyluracil (E,Z-
10a).
1
This mixture of isomers was obtained as an oil; H nmr: δ 0.80
(m, CH ), 1.20 (m, CH CH (CH ) CH ), 1.54-1.63 (m,
3
2
2
2 5
3
CH CH (CH ) CH ), 3.68-3.78 (m, CH CH (CH ) CH and
2
2
2 5
3
2
2
2 5
3
COOCH ), 3.91 (t, J = 6.8 Hz, CH CH (CH ) CH ), 5.81 (d, J =
3
2
2
2 5
3
12.8 Hz, CH=CH of (Z)-isomer), 6.97 (d, J = 16.1 Hz, CH=CH of
(E)-isomer), 7.12 (d, J = 12.8 Hz, CH=CH of (Z)-isomer), 7.26
(d, J = 16.1 Hz, CH=CH of (E)-isomer), 7.37 (s, 6-H of (E)-iso-
General Procedure for the Wittig Reaction of Aldehydes 5, 6 and
7 with the Semistabilized Ylides 8c and 8d.
13
mer), 9.10 (s, 6-H of (Z)-isomer); C nmr: δ 13.9 (CH ), 22.5,
3
I) To a stirred suspension of 4-nitrobenzylltriphenylphospho-
nium chloride or 4-pyridinylmethyltriphenylphosphonium chlo-
ride (1.5 mmole) in dry benzene (5 ml) under argon atmosphere
was added potassium tert-butoxide (0.224 g, 2 mmoles). After
stirring for 1 hour, 1 mmole of the corresponding aldehyde was
added and the mixture was stirred for additional 2 hours. The
reaction mixture was diluted with water and extracted with ether.
The organic layers were combined, dried over sodium sulfate and
concentrated. The residue was chromatographed on a silica gel
column with hexane-ethyl acetate (2:1 for the reactions of 5, 5:1
for the reactions of 6, 3:1 for the reactions of 7) as the eluent. In
all cases it was possible to isolate from the column fractions with
separated pure (E)- and (Z)-isomers.
II) 4-Nitrobenzylltriphenylphosphonium chloride or 4-
pyridinylmethyltriphenyl phosphonium chloride chloride (1.5
mmoles) and aldehyde (1mmole) were dissolved in methylene
chloride (5 ml) and the solution was stirred with an aqueous 10 %
NaOH solution (5 ml) at room temperature until consumption of
the aldehyde. The two layers were separated and the aqueous layer
was extracted with methylene chloride. The combined organic
layers were extracted once with water, dried over sodium sulfate
and concentrated. The residue was treated as in procedure I.
26.3, 26.9, 27.4, 28.8, 29.0, 29.05, 29.1, 31.6, 31.7 41.6 and 47.0
((CH ) CH and COOCH ), 107.3 and 108.8 (C-5), 116.3, 118.3
2 7
3
3
135.7 and 136.8 (CH=CH), 144.3 and 146.3 (C-6), 150.1 and
151.2 (C-2), 160.9 and 162.1 (C-4), 167.2 and 168.0 (COOCH );
3
+
ms: m/z 420 (M , 38% rel. int.).
Anal. Calcd. for C
H N O : C, 68.54; H, 9.59; N, 6.66.
24 40 2 4
Found: C, 68.47; H, 9.36; N, 7.06.
2,4-Dimethoxy-5-[(E)-3-methoxy-3-oxo-1propenyl]pyrimidine
(E-11a).
1
This compound was obtained as a white solid mp 118-120°; H
nmr: δ 3.72 (s, 3H, OCH ), 3.95 (s, 3H, OCH ), 4.01 (s, 3H,
3
3
OCH ), 6.52 (d, J = 16.0 Hz, 1H, CH=CH), 7.52 (d, J = 16.0 Hz,
3
13
1H, CH=CH), 8.29 (s, 1H, 6-H); C nmr: δ 51.6, 54.2 and 55.1
(OCH ), 110.3 (C-5), 119.0 and 136.0 (CH=CH), 159.6 (C-6),
3
165.3, 167.4 and 168.9 (C-2, C-4 and COOCH ); ms: m/z 224
3
+
(M , 84% rel. int.).
Anal. Calcd. for C
H N O : C, 53.57; H, 5.39; N, 12.49.
10 12 2 4
Found: C, 54.19; H, 5.69; N, 12.29.
2,4-Dimethoxy-5-[(Z)-3-methoxy-3-oxo-1-propenyl]pyrimidine
(Z-11a).
1
This compound was obtained as a white solid mp 87-90°; H
5-[(E)-3-Methoxy-3-oxo-1propenyl]-1-octyluracil (E-9a).
nmr: δ 3.71 (s, 3H, OCH ), 4.01 (s, 3H, OCH ), 4.02 (s, 3H,
3
3
1
This compound was obtained as a white solid mp 116-118°; H
OCH ), 5.99 (d, J = 12.7 Hz, 1H, CH=CH), 6.91 (d, J = 12.7 Hz,
3
13
nmr: δ 0.80 (t, J = 6.4 Hz, 3H, CH ), 1.23 (m, 10H, CH CH -
1H, CH=CH), 8.66 (s, 1H, 6-H); C nmr: δ 51.4, 54.1 and 55.0
3
2
2
(CH ) CH ), 1.65 (m, 2H, CH CH (CH ) CH ), 3.70 (s, 3H,
(OCH ), 109.9 (C-5), 120.0 and 134.3 (CH=CH), 159.5 (C-6),
2 5
3
2
2
2 5
3
3

1140
E. Coutouli-Argyropoulou and C. Zachariadou
Vol. 42
165.2, 166.3 and 168.4 (C-2, C-4 and COOCH ); ms: m/z 224
(M , 74% rel. int.).
Anal. Calcd. for C H N O : C, 63.62; H, 7.63; N, 10.60.
28 40 4 6
Found: C, 63.22; H, 7.81; N, 10.28.
3
+
Anal. Calcd. for C
Found: C, 53.23; H, 5.79; N, 12.19.
H N O : C, 53.57; H, 5.39; N, 12.49.
10 12 2 4
2,4-Dimethoxy-5-[(E)- 2-(2,4-dinitrophenyl)ethenyl]pyrimidine
(E-11b).
5-[(E)-2-(2,4-Dinitrophenyl)ethenyl]-1octyluracil (E-9b).
This compound was obtained as a yellow solid mp 147- 150°;
This compound was obtained as a yellow solid mp 170-173°;
1
H nmr: δ 4.05 (s, 3H, OCH ), 4.13 (s, 3H, OCH ), 7.21 (d, J =
3
3
1
16.1 Hz, 1H, CH=CH), 7.78 (d, J = 16.1 Hz, 1H, CH=CH), 7.96
(d, J = 7.0 Hz, 1H, Ar-H), 8.43 (dd, J = 7.0, 1.9 Hz, 1H, Ar-H),
H nmr: δ 0.87 (t, J = 6.4 Hz, 3H, CH ), 1.28 (m, 10H,
3
CH CH (CH ) CH ), 1.74 (m, 2H, CH CH (CH ) CH ), 3.62
2
2
2 5
3
2
2
2 5
3
13
8.45 (s, 1H, 6-H), 8.82 (d, J = 1.9 Hz, 1H, Ar-H); C nmr: δ 54.5
(t, J = 7.4 Hz, 2H, CH CH (CH ) CH ), 7.01 (d, J = 16.1 Hz, 1H,
2
2
2 5
3
and 55.2 (OCH ), 111.6 (C-5), 120.7, 122.5, 127.1, 129.1, 128.8,
CH=CH), 7.49 (s, 1H, 6-H), 7.85 (d, J = 16.1 Hz, 1H, CH=CH),
7.89 (d, J = 6.4 Hz, 1H, Ar-H), 8.40 (dd, J = 6.4, 1.4 Hz, 1H, Ar-
3
139.0, 146.2 and 147.3 (CH=CH and C-Ar), 158.3 (C-6), 165.1
+
13
(C-4), 168.5 (C-2): ms: m/z 332 (M , 45% rel. int.).
H), 8.67 (br s, 1H, NH), 8.79 (d, J = 1.4 Hz, 1H, Ar-H); C nmr:
δ 14.0 (CH ), 22.6, 26.4, 29.1, 29.2, 29.7 and 31.7
Anal. Calcd. for C H N O : C, 50.61; H, 3.64; N, 16.86.
Found: C, 50.63; H, 4.04; N, 16.59.
3
14 12 4 6
(CH (CH ) CH ), 49.1 (CH (CH ) CH ), 110.9 (C-5), 120.7,
2
2 6
3
2
2 6
3
121.9, 127.1, 128.4, 128.9 (CH=CH and C-Ar), 138.7 (C-Ar),
143.2 (C-6), 146.3 and 147.4 (C-Ar), 149.4 (C-2), 161.5 (C-4);
ms: m/z 416 (M , 35% rel. int.).
2,4-Dimethoxy-5-[(Z)- 2-(2,4-dinitrophenyl)ethenyl]pyrimidine
(Z-11b).
+
This compound was obtained as a yellow solid mp 145-148°;
Anal. Calcd. for C
Found: C, 57.29; H, 5.81; N, 13.05.
H N O : C, 57.69; H, 5.81; N, 13.45.
20 24 2 6
1
H nmr: δ 3.91 (s, 3H, OCH ), 3.94 (s, 3H, OCH ), 6.79 (d, J =
3
3
11.6 Hz, 1H, CH=CH), 6.98 (d, J = 11.6 Hz, 1H, CH=CH), 7.42
(d, J = 8.4 Hz, 1H, Ar-H), 7.77 (s, 1H, 6-H), 8.25 (dd, J = 8.4, 1.9
5-[(Z)-2-(2,4-Dinitrophenyl)ethenyl]-1octyluracil (Z-9b).
13
Hz, 1H, Ar-H), 8.92 (d, J = 1.9 Hz, 1H, Ar-H); C nmr: δ 54.1
This compound was obtained only as a solid mixture with the
and 55.0 (OCH ), 110.2 (C-5), 120.5, 125.5, 126.1, 127.2, 132.8,
(E)-isomer. Its proton nmr chemical shifts were assigned from
3
1
1
139.7, 146.8 and 147.7 (CH=CH and C-Ar), 158.3 (C-6), 164.9
the H nmr of the mixture; H nmr: δ 0.87 (m, CH ), 1.28 (m,
3
+
(C-4), 168.4 (C-2): ms: m/z 332 (M , 28% rel. int.).
CH CH (CH ) CH ), 1.60 (m, CH CH (CH ) CH ), 3.57 (t, J =
2
2
2 5
3
2
2
2 5
3
Anal. Calcd. for C
H N O : C, 50.61; H, 3.64; N, 16.86.
7.1 Hz, CH CH (CH ) CH ), 6.60 (d, J = 12.2 Hz, CH=CH),
14 12 4 6
2
2
2 5
3
6.90 (s, 6-H), 6.97 (d, J = 12.2 Hz, CH=CH), 7.57 (d, J = 8.3 Hz,
Ar-H), 8.45 (dd, J = 6.4, 1.6 Hz, Ar-H), 8.45 (br s, NH), 8.94 (d,
J = 1.6 Hz, Ar-H).
Found: C, 50.91; H, 3.76; N, 16.70.
5-[(E)-2-(4-Nitrophenyl)ethenyl]-1-octyluracil (E- 9c).
This compound was obtained as a yellow solid mp 173-176°;
5-[(E)-2-(2,4-Dinitrophenyl)ethenyl]-1,3-dioctyluracil (E-10b).
1
H nmr: δ 0.87 (t, J = 6.5 Hz, 3H, CH ), 1.28 (m, 10H,
2 2 2 5 3 2 2 2 5 3
3
This compound was obtained as a yellow solid mp 131-133°;
CH CH (CH ) CH ), 1.64 (m, 2H, CH CH (CH ) CH ), 3.81
1
H nmr: δ 0.87 (m, 6H, CH ), 1.27-1.32 (m, 20H,
(t, J = 7.3 Hz, 2H, CH CH (CH ) CH ), 6.90 (d, J = 16.4 Hz, 1H,
2 2 2 5 3
CH=CH), 7.38 (s, 1H, 6-H), 7.57 (d, J = 8.7 Hz, 2H, Ar-H), 7.64
3
CH CH (CH ) CH ), 1.63-1.75 (m, 4H, CH CH (CH ) CH ),
2
2
2 5
3
2
2
2 5
3
3.83 (t, J = 7.4 Hz, 2H, CH CH (CH ) CH ), 3.97 (t, J = 7.4 Hz,
(d, J = 16.4 Hz, 1H, CH=CH), 8.20 (d, J = 8.7 Hz, 2H, Ar-H),
2
2
2 5
3
13
2H, CH CH (CH ) CH ), 7.08 (d, J = 16.1 Hz, 1H, CH=CH),
8.71 (br s, 1H, NH);
29.2, 29.7 and 31.7 (CH (CH ) CH ), 49.3 (CH (CH ) CH ),
C nmr: δ 14.0 (CH ), 22.6, 26.4, 29.1,
2 2 6 3 2 2 6 3
2
2
2 5
3
3
7.50 (s, 1H, 6-H), 7.84 (d, J = 16.1 Hz, 1H, CH=CH), 7.90 (d, J =
9.0 Hz, 1H, Ar-H), 8.37 (dd, J = 9.0, 1.6 Hz, 1H, Ar-H), 8.76 (d,
111.4 (C-5), 124.1, 126.7, 127.7, 129.3, 142.8, 143.9 and 146.8
(CH=CH, C-6 and C-Ar), 149.4 (C-2), 161.7 (C-4); ms: m/z 371
13
J = 1.6 Hz, 1H, Ar-H); C nmr: δ 14.0 (CH ), 22.6, 26.4, 26.9,
3
+
27.4, 29.0, 29.1, 29.2, 31.6 and 31.7 (CH (CH ) CH ), 41.8 and
(M , 51% rel. int.).
2
2 6
3
50.4 (CH (CH ) CH ), 110.0 (C-5), 120.6, 120.9, 126.9, 128.7,
Anal. Calcd. for C
H N O : C, 64.67; H, 6.78; N, 11.31.
20 25 3 4
2
2 6
3
129.7 and 138.9 (CH=CH and C-Ar), 141.4 (C-6), 146.0 and
147.2 (C-Ar), 150.2 (C-2), 161.4 (C-4); ms: m/z 528 (M , 35%
rel. int.).
Found: C, 64.47; H, 6.38; N, 11.15.
+
5-[(Z)-2-(4-Nitrophenyl)ethenyl]-1-octyluracil (Z- 9c).
1
This compound was obtained as a yellow solid mp 108-110°; H
Anal. Calcd. for C
H N O : C, 63.62; H, 7.63; N, 10.60.
28 40 4 6
nmr: δ 0.87 (t, J = 6.8 Hz, 3H, CH ), 1.32 (m, 10H,
Found: C, 63.87; H, 7.30; N, 10.27.
3
CH CH (CH ) CH ), 1.43 (m, 2H, CH CH (CH ) CH ), 3.54 (t, J
2
2
2 5
3
2
2
2 5
3
5-[(Z)-2-(2,4-Dinitrophenyl)ethenyl]-1,3-dioctyluracil (Z-10b).
This compound was obtained as a yellow solid mp 107-110°;
= 7.4 Hz, 2H, CH CH (CH ) CH ), 6.53 (d, J = 12.2 Hz, 1H,
2
2
2 5
3
CH=CH), 6.68 (d, J = 12.2 Hz, 1H, CH=CH), 6.97 (s, 1H, 6-H), 7.49
(d, J = 8.6 Hz, 2H, Ar-H), 8.19 (d, J = 8.6 Hz, 2H, Ar-H), 9.38 (br s,
1
H nmr: δ 0.89 (m, 6H, CH ), 1.12-1.42 (m, 24H,
3
13
CH (CH ) CH ), 3.56 (t, J = 7.1 Hz, 2H, CH CH (CH ) CH ),
1H, NH); C nmr: δ 14.0 (CH ), 22.5, 26.2, 29.0, 29.2, 29.7 and
2
2 6
3
2
2
2 5
3
3
3.89 (t, J = 7.4 Hz, 2H, CH CH (CH ) CH ), 6.67 (d, J = 11.8
31.7 (CH (CH ) CH ), 48.9 (CH (CH ) CH ), 109.9 (C-5), 123.7,
2
2
2 5
3
2 2 6 3 2 2 6 3
Hz, 1H, CH=CH), 6.82 (s, 1H, 6-H), 6.88 (d, J = 11.8 Hz, 1H,
CH=CH ), 7.58 (d, J = 8.4 Hz, 1H, Ar-H), 8.32 (dd, J = 8.4, 2.5
124.1, 129.1, 129.3, 142.9, 143.8 and 146.7 (CH=CH, C-6 and C-
Ar), 150.0 (C-2), 162.8 (C-4); ms: m/z 371 (M , 48% rel. int.).
+
13
Hz, 1H, Ar-H), 8.92 (d, J = 2.5 Hz, 1H, Ar-H); C nmr: δ 14.0
Anal. Calcd. for C
H N O : C, 64.67; H, 6.78; N, 11.31.
20 25 3 4
(CH ), 22.5, 22.6, 26.2, 26.5, 26.9, 27.0, 27.4, 29.0, 29.1, 29.2,
Found: C, 65.02; H, 6.99; N, 10.98.
3
31.7 and 31.8 (CH (CH ) CH ), 41.8 and 50.0 (CH (CH ) -
2
2 6
3
2
2 6
5-[(E)-2-(4-Nitrophenyl)ethenyl]-1,3-dioctyluracil (E-10c).
CH ), 108.9 (C-5), 125.5, 126.1, 127.1, 127.5, 132.8 and 139.9
3
1
(CH=CH and C-Ar), 141.7 (C-6), 146.7 and 148.0 (C-Ar), 150.4
This compound was obtained as an oil; H nmr: δ 0.88 (m, 6H,
+
(C-2), 161.4 (C-4); ms: m/z 528 (M , 31% rel. int.).
CH ), 1.26-1.34 (m, 20H, CH CH (CH ) CH ), 1.66-1.75 (m, 4H,
3 2 2 2 5 3

Sep-Oct 2005
Synthesis of 5-Substituted Uracils and 2,4-Dimethoxypyrimidines
1141
CH CH (CH ) CH ), 3.82 (t, J = 7.1 Hz, 2H, CH CH -
120.6, 125.0, 126.6, 140.8, 145.0 and 150.1 (CH=CH, C-Pyr. and
C-6), 150.3 (C-2), 161.6 (C-4); ms: m/z 439 (M , 48% rel. int.).
2
2
2 5
3
2
2
+
(CH ) CH ), 4.00 (t, J = 7.7 Hz, 2H, CH CH -(CH ) CH ), 6.94
2 5
3
2
2
2 5
3
(d, J = 16.7 Hz, 1H, CH=CH), 7.37 (s, 1H, 6-H), 7.55 (d, J = 16.7
Hz, 1H, CH=CH), 7.63 (d, J = 9.0 Hz, 2H, Ar-H), 8.19 (d, J = 9.0
Anal. Calcd. for C
Found: C, 73.58; H, 9.19; N, 9.90.
H N O : C, 73.76; H, 9.40; N, 9.56.
27 41 3 2
13
Hz, 2H, Ar-H); C nmr: δ 14.0 (CH ), 22.6, 26.5, 27.0, 27.5, 29.1,
3
1,3-dioctyl-5-[(Z)-2-(4-pyridinyl)ethenyl]uracil (Z-10d).
29.2, 29.3, 29.7, 31.7, 31.8, and 31.9 (CH (CH ) CH ), 41.8 and
2
2 6
3
1
50.3 (CH (CH ) CH ), 110.5 (C-5), 124.1, 125.1, 126.6, 126.9,
This compound was obtained as a oil; H nmr: δ 0.87 (t, J = 6.4
2
2 6
3
141.0, 144.2 and 146.6 (CH=CH, C-6 and C-Ar), 150.2 (C-2),
Hz, 6H, CH ), 1.24-1.64 (m, 24H, CH (CH ) CH ), 3.53 (t, J =
3 2 2 6 3
+
161.6 (C-4); ms: m/z 483 (M , 100% rel. int.).
7.1 Hz, 2H, CH CH (CH ) CH ), 3.96 (t, J = 7.4 Hz, 2H,
2 2 2 5 3
Anal. Calcd. for C
H
N O : C, 69.54; H, 8.54; N, 8.69.
CH CH (CH ) CH ), 6.52 (d, J = 12.2 Hz, 1H, CH=CH), 6.57
28 41
3
4
2 2 2 5 3
Found: C, 69.51; H, 8.58; N, 9.04.
(d, J = 12.2 Hz, 1H, CH=CH), 6.95 (s, 1H, 6-H), 7.22 (d, J = 5.5
13
Hz, 2H, Pyr-H), 8.55 (d, J = 5.5 Hz, 2H, Pyr-H); C nmr: δ 14.0
5-[(Z,)-2-(4-Nitrophenyl)ethenyl]-1,3-dioctyluracil (Z-10c).
(CH ), 22.6, 26.2, 26.9, 27.5, 29.0, 29.1, 29.2, 29.3, 31.6 and
3
1
This compound was obtained as an oil; H nmr: δ 0.88 (m, 6H,
31.7 (CH (CH ) CH ), 41.7 and 49.7 (CH (CH ) CH ), 108.9
2
2 6
3
2
2 6
3
CH ), 1.26-1.34 (m, 20H, CH CH (CH ) CH ), 1.44-1.62 (m, 4H,
(C-5), 120.0, 123.0, 124.7, 127.5, 140.7 and 145.0 (CH=CH,
3
2
2
2 5
3
+
CH CH (CH ) CH ), 3.55 (t, J = 7.1 Hz, 2H, CH CH (CH ) -
C-Pyr. and C-6), 150.3 (C-2), 162.2 (C-4); ms: 439 (M , 68%
2
2
2 5
3
2
2
2 5
CH ), 3.96 (t, J = 7.7 Hz, 2H, CH CH (CH ) CH ), 6.53 (d, J =
rel. int.).
3
2
2
2 5
3
12.2 Hz, 1H, CH=CH), 6.64 (d, J = 12.2 Hz, 1H, CH=CH), 6.96 (s,
1H, 6-H), 7.49 (d, J = 8.4 Hz, 2H, Ar-H), 8.18 (d, J = 8.4 Hz, 2H,
Anal. Calcd. for C
Found: C, 73.72; H, 9.09; N, 9.60.
H N O : C, 73.76; H, 9.40; N, 9.56.
27 41 3 2
13
Ar-H); C nmr: δ 14.0 (CH ), 22.5, 22.6, 26.2, 26.9, 27.5, 29.1,
3
2,4-Dimethoxy-5-[(E)-2-(4-pyridinyl)ethenyl]pyrimidine (E-
11d).
28.9, 29.1, 29.2, 31.6, and 31.7 (CH (CH ) CH ), 41.7 and 49.7
2
2 6
3
(CH (CH ) CH ), 109.0 (C-5), 123.9, 124.7, 128.3, 129.3, 140.8,
2
2 6
3
1
144.0 and 146.5 (CH=CH, C-6 and C-Ar), 150.5 (C-2), 162.1
This compound was obtained as a white solid mp 112-114°; H
+
(C-4); ms: m/z 483 (M , 100% rel. int.).
nmr: δ 4.03 (s, 3H, OCH ), 4.10 (s, 3H, OCH ), 7.10 (d, J = 16.7
3
3
Anal. Calcd. for C
H N O : C, 69.54; H, 8.54; N, 8.69.
Hz, 1H, CH=CH), 7.23 (d, J = 16.7 Hz, 1H, CH=CH), 7.37 (d, J
= 6.4 Hz, 2H, Pyr-H), 8.42 (s, 1H, 6-H), 8.56 (d, J = 6.4 Hz, 2H,
28 41 3 4
Found: C, 69.64; H, 8.78; N, 8.34.
13
Pyr-H); C nmr: δ 54.2 and 55.0 (OCH ), 111.8 (C-5), 120.8,
3
2,4-Dimethoxy-5-[(E)- 2-(4-nitrophenyl)ethenyl]pyrimidine (E-
11c).
124.5, 126.9, 145.3 and 149.4 (CH=CH and C-Pyr), 157.0 (C-6),
+
164.6 (C-4), 168.3 (C-2): ms: m/z 243 (M , 100% rel. int.).
This compound was obtained as a yellow solid mp 137-140°;
Anal. Calcd. for C
Found: C, 63.98; H, 5.50; N, 16.99.
H N O : C, 64.19; H, 5.39; N, 17.27.
13 13 3 2
1
H nmr: δ 4.04 (s, 3H, OCH ), 4.12 (s, 3H, OCH ), 7.18 (d, J =
3
3
16.7 Hz, 1H, CH=CH), 7.25 (d, J = 16.7 Hz, 1H, CH=CH), 7.62
(d, J = 9.0 Hz, 2H, Ar-H), 8.22 (d, J = 9.0 Hz, 2H, Ar-H) 8.43 (s,
2,4-Dimethoxy-5-[(Z)-2-(4-pyridinyl)ethenyl]pyrimidine (Z-
11d).
13
1H, 6-H); C nmr: δ 54.3 and 55.1 (OCH ), 112.0 (C-5), 124.1,
3
1
124.3, 126.8, 127.4, 129.2 and 144.0 (CH=CH and C-Ar), 157.0
(C-6), 164.7 (C-4), 168.4 (C-2): ms: m/z 287 (M , 45% rel. int.).
This compound was obtained as a white solid mp 88-91°; H
nmr: δ 3.95 (s, 3H, OCH ), 3.97 (s, 3H, OCH ), 6.57 (s, 2H,
CH=CH), 7.08 (d, J = 5.1 Hz, 2H, Pyr-H), 7.97 (s, 1H, 6-H), 8.48
(d, J = 5.1 Hz, 2H, Pyr-H); C nmr: δ 54.1 and 54.9 (OCH ),
111.0 (C-5), 123.0, 124.4, 130.0, 144.7 and 150.1 (CH=CH and
C-Pyr), 157.8 (C-6), 164.7 (C-4), 168.5 (C-2): ms: m/z 243 (M ,
100% rel. int.).
+
3
3
Anal. Calcd. for C
H N O : C, 58.53; H, 4.56; N, 14.63.
14 13 3 4
13
Found: C, 58.43; H, 4.59; N, 14.66.
3
2,4-Dimethoxy-5-[(Z)- 2-(4-nitrophenyl)ethenyl]pyrimidine (Z-
11c).
+
This compound was obtained as a yellow solid mp 118-120°;
Anal. Calcd. for C
Found: C, 64.02; H, 5.62; N, 17.05.
H N O : C, 64.19; H, 5.39; N, 17.27.
13 13 3 2
1
H nmr: δ 3.98 (s, 6H, OCH ), 6.61 (d, J = 12.2 Hz, 1H,
3
CH=CH), 6.71 (d, J = 12.2 Hz, 1H, CH=CH), 7.37 (d, J = 9.0 Hz,
Demethylation of Compound 11c.
13
2H, Ar-H), 7.96 (s, 1H, 6-H), 8.12 (d, J = 9.0 Hz, 2H, Ar-H);
C
nmr: δ 54.1 and 54.9 (OCH ), 110.9 (C-5), 123.8, 124.2, 128.3,
A mixture of (E)- (Z)-isomers of 11c (0.057 g, 0.2 mmoles)
was heated with sodium iodide (0.1 g) in glacial acetic acid (3
ml) at 100° for 1 hour. The solvent was removed under reduced
pressure and the residue was chromatographed on a silica gel col-
umn with 3% methanol in methylene chloride as the eluent. From
the column 0.047 g (92 % yield) of the demethylated uracil 12
were obtained.
3
129.2, 129.3 and 143.8 (CH=CH and C-Ar), 157.8 (C-6), 164.7
+
(C-4), 168.6 (C-2): ms: m/z 287 (M , 48% rel. int.).
Anal. Calcd. for C
H N O : C, 58.53; H, 4.56; N, 14.63.
14 13 3 4
Found: C, 58.29; H, 4.50; N, 14.38.
1,3-dioctyl-5-[(E)-2-(4-pyridinyl)ethenyl]uracil (E-10d).
1
This compound was obtained as a oil; H nmr: δ 0.91 (t, J = 6.4
5-[(E)-2-(4-Nitrophenyl)ethenyl]uracil (12).
Hz, 6H, CH ), 1.30-1.36 (m, 20H, CH CH (CH ) CH ), 1.68-
3
2
2
2 5
3
1.74 (m, 4H, CH CH (CH ) CH ), 3.84 (t, J = 7.3 Hz, 2H,
This compound was obtained as a yellow solid which does not
2
2
2 5
3
1
CH CH (CH ) CH ), 4.02 (t, J = 7.7 Hz, 2H, CH CH -
melts up to 300°; H nmr (DMSO-d ): δ 7.11 (d, J = 16.5 Hz, 1H,
2
2
2 5
3
2
2
6
(CH ) CH ), 7.00 (d, J = 16.1 Hz, 1H, CH=CH), 7.32 (d, J = 4.8
CH=CH), 7.57 (d, J = 16.5 Hz, 1H, CH=CH), 7.62 (d, J = 8.2 Hz,
2H, Ar-H), 7.75 (s, 1H, 6-H), 8.12 (d, J = 8.2 Hz, 2H, Ar-H),
2 5
3
Hz, 2H, Pyr-H), 7.38 (s, 1H, 6-H), 7.50 (d, J = 16.1 Hz, 1H,
13
13
CH=CH), 8.56 (d, J = 4.8 Hz, 2H, Pyr-H); C nmr: δ 14.1 (CH ),
11.29 (br s, 2H, NH); C nmr: δ 109.0 (C-5), 123.7, 124.6,
3
22.6, 26.3, 26.5, 27.0, 27.6, 29.1, 29.2, 29.3, 31.7 and 31.8
126.3, 126.4, 142.0, 144.8 and 145.6 (CH=CH, C-Ar and C-6),
+
(CH (CH ) CH ), 41.8 and 50.3 (CH (CH ) CH ), 110.0 (C-5),
150.3 (C-2), 162.8 (C-4); ms: m/z 259 (M , 48% rel.int.).
2
2 6
3
2
2 6
3

1142
E. Coutouli-Argyropoulou and C. Zachariadou
Vol. 42
Med. Chem., 45, 2032 (2002); [l] D. G. Harris, J. Y. Shao, B. D. Morrow
and S. S. Zimmerman, Nucleosides nucleotides & Nucleic acids, 23, 555
(2004).
[3a] E. De Clercq, J. Balzarini, P. F. Torrence, M. P. Mertes, C. L.
Schmidt, D. Shugar, P. J. Barr, A. S. Jones, G. Verhelst and R. T. Walker,
Molecular Pharmacology, 19, 321 (1981); [b] E. De Clercq, J. Balzarini,
J. Descamps, C. F. Bigge, C. T. –C. Chang, P. Kalaritis and M. P. Mertes,
Biochem. Pharmacol., 30, 495 (1981); [c] L. A. Al-Razzak, D.
Schwepler, C. J. Decedue, J. Balzarini E. De Clercq and M. P. Mertes, J.
Med. Chem., 30, 409 (1987).
[4a] C. F. Bigge, P. Kalaritis, J. R. Deck and M. P. Mertes, J. Am.
Chem. Soc., 102, 2033 (1980); [b] S. G. Rahim, M. J. H. Duggan, R. T.
Walker, A. S. Jones, R. L. Dyer, J. Balzarini and E. De Clercq, Nucleic
Acids Res., 10, 5285 (1982); [c] D. E. Bergstrom, J. L. Ruth, P. A. Reddy
and E. De Clercq, J. Med. Chem., 27, 279 (1984); [d] N. G. Kundu, P.
Das, J. Balzarini and E. De Clercq, Biorganic & Medicinal Chemistry, 5,
2011 (1997); [e] S. I. Khan and M. W. Grinstaff, J. Org. Chem., 64, 1077
(1999).
[5a] R. A. Sharma and M. Bobek, J. Org. Chem., 40, 2377 (1975);
[b] J. Perman, R. A. Sharma and M. Bobek, Tetrahedron Lett., 2427
(1976); [c] P. L. Coe, M. R. Harnden, A. S. Jones, S. A. Noble and R. T.
Walker, J. Med. Chem., 25, 1329 (1982); [d] K. Hirota, Y. Kitade, K.
Shimada and Y. Maki, J. Org. Chem., 50, 1512 (1985); [e] M. Bobek, I.
Kavai and E. De Clercq, J. Med. Chem., 30, 1494 (1987); [f] P. Matyus,
M. Nieger and H. Wamhoff, Phosphorus Sulfur Silicon Relat. Elem., 63,
323 (1991).
Anal. Calcd. for C H N O : C, 55.60; H, 3.50; N, 16.21.
Found: C, 55.46; H, 3.35; N, 15.97.
12
9 3 4
Isomerization of Z-10c to E-10c.
A solution of Z-10c (0.048 g, 0.1 mmole) in glacial acetic acid
(2 ml) was heated with sodium iodide (0.05 g) at 100° for 1 hour.
The solvent was removed under reduced pressure and the residue
taken up in diethyl ether (10 ml) and washed with water (2 x 10
ml). The organic layer was dried over sodium sulfate and concen-
trated to leave 0.04 g (83%) of E-10c.
Isomerization of the Mixture E,Z-11a to E-11a.
A solution of 1:1 mixture of E,Z-11a (0.067 g, 0.3 mmoles) in
carbon tetrachloride (1 ml) was treated with thiophenol (0.017g,
0.15 mmoles) and 2,2'-azobis(2-methylpropionitrile) (AIBN,
0.008 g, 0.05 mmoles) at 80° for 3 hours. The reaction mixture
was cooled to room temperature and taken up in ethyl acetate (10
ml) and washed with an 0.01 N NaOH aqueous solution (10 ml).
The organic layer was dried over sodium sulfate and concentrated
to leave an oil (0.07 g), which contained only (E)-isomer contam-
1
inated with aromatic thiol product, as it was shown by H NMR
spectrum.
REFERENCES AND NOTES
[6] E. Coutouli-Argyropoulou and P. Pilanidou, Tetrahedron
Lett., 44, 3755 (2003).
[1a] Y. Uto, H. Konto, M. Abe, T. Suzuki and S. Takenaka, Anal.
Biochem., 250, 122 (1997); [b] A. Anne, B. Blanc and J. Moiroux,
Bioconjugate Chem., 12, 396 (2001); [c] E. Coutouli-Argyropoulou, M.
Tsitabani, G. Petrantonakis, A. Terzis and C. Raptopoulou, Org. Biomol.
Chem., 1, 1382 (2003).
[7] A. Ono, T. Okamoto, M. Inada, H. Nara and A. Matsuda,
Chem. Pharm. Bull., 42, 2231 (1994).
[8a] A. Johnson, Ylides and Imines of Phosphorus, John Wiley &
Sons, New York, 1993; [b] O. I. Kolodiazhnyi, Phosphorus Ylides.
Chemistry and Application in Organic Synthesis, John Wiley & Sons,
New York, 1999; [c] B. R. Maryanoff and A. B. Reitz, Chem. Rev., 89,
863 (1989).
[9a] T. L. V. Ulbricht, J. Chem. Soc., 3345 (1961); [b] B. Das and
N. G. Kundu, Synth. Commun., 18, 855 (1988).
[10 J. Wang, J. Morral, C. Hendrix and P. Herdewijn, J. Org.
Chem., 66, 8478 (2001).
[11a] R. Ketcham, D. Jambotkar and L. Martinelli, J. Org. Chem.,
27, 4666 (1962); [b] J. J. Pappas and E. Gancher, J. Org. Chem., 31, 1287
(1966); [c] P. Carsky, S. Hünig, I. Stemmler and D. Scheutzow, Liebigs
Ann. Chem., 291 (1980).
[12] W. Schmidt-Nickels and T. B. Johnson, J. Am. Chem. Soc., 52,
4511 (1930).
[2a] A. S. Jones, G. Verhelst and R. T. Walker, Tetrahedron Lett.,
4415 (1979); [b] A. S. Jones, S. G. Rahim, R. T. Walker and E. De Clercq,
J. Med. Chem., 24, 759 (1981); [c] J. Goodchild, R. A. Porter, R. H.
Raper, I. S. Sim, R. M. Upton, J. Viney and H. J. Wadsworth, J. Med.
Chem., 26, 1252 (1983); [d] M. C. Perlman, K. A. Watanabe, R. F.
Schinazi and J. J. Fox J. Med. Chem., 28, 741 (1985); [e] E. De Clercq, C.
Desgranges, P. Herdewijn, I. S. Sim, A. S. Jones, M. J. McLean and R. T.
Walker, J. Med. Chem., 29, 213 (1986); [f] S. Izuta and M. Saneyoshi,
Chem. Pharm. Bull., 35, 4829 (1987); [g] N. G. Kundu and L. N.
Chaudhuri, J. Chem. Soc. Perkin Trans. 1, 1677 (1991); [h] P. Wigerinck,
C. Pannecouque, R. Snoeck, P. Claes, E. De Clercq and P. Herdewijn, J.
Med. Chem., 34, 2383 (1991); [i] R. Kumar, E. E. Knaus and L. I. Wiebe,
J. Heterocyclic Chem., 28, 1917 (1991); [j] Y. Choi, L. Li, S. Grill, E.
Gullen, C. S. Lee, G. Gumina, E. Tsujii, Y. Cheng and C. K. Chu, J. Med.
Chem., 43, 2538 (2000); [k] R. Kumar, M. Nath and D. L. J. Tyrrell, J.
[13] M. Salas, B. Gordillo and F. J. González, ARKIVOC, (xi) 72
(2003).
[14] E. L. Stogryn, J. Heterocyclic Chem., 11, 251 (1974).