The silyl method for the synthesis of 1[-2(phenoxy)ethyl]uracils

Article abstract of DOI:10.1007/s10593-005-0246-9

A modification of the method for the synthesis of N₍₁₎- substituted derivatives of uracil is proposed using the Gilbert-Johnson reaction, which consists of the alkylation of 5-substituted 2,4- bis(trimethylsiloxy)pyrimidines with 1-bromo-2-(phenoxy)ethanes of low reactivity at 180-185° without solvent. The corresponding 1-[2-(phenoxy)ethyl]uracils, which were obtained in 55-74% yield, contained no impurities of the N₍₁₎, N₍₃₎-disubstituted compounds. 2005 Springer Science+Business Media, Inc.

Full text of DOI:10.1007/s10593-005-0246-9

Chemistry of Heterocyclic Compounds, Vol. 41, No. 7, 2005
THE SILYL METHOD FOR THE SYNTHESIS
OF 1[-2(PHENOXY)ETHYL]URACILS*
M. S. Novikov and A. A. Ozerov
A modification of the method for the synthesis of N(1)-substituted derivatives of uracil is proposed using
the Gilbert–Johnson reaction, which consists of the alkylation of 5-substituted
2,4-bis(trimethylsiloxy)pyrimidines with 1-bromo-2-(phenoxy)ethanes of low reactivity at 180-185°
without solvent. The corresponding 1-[2-(phenoxy)ethyl]uracils, which were obtained in 55-74% yield,
contained no impurities of the N(1),N(3)-disubstituted compounds.
Keywords: 2,4-bis(trimethylsiloxy)pyrimidine, 1-bromo-2-(phenoxy)ethane, N(1)-alkylation, the
Gilbert–Johnson reaction.
The silyl modification of the Gilbert–Johnson reaction is widely used in the synthesis of pyrimidine
nucleosides and their alkyl analogs. It is based on the alkylation of 2,4-bis(trimethylsiloxy)pyrimidines with
highly reactive alkyl halides such as α-halo ethers [1-3] or α-halo sugars [4,5]. It is thought [6] that the first
product of the interaction of the alkylating agent and 2,4-bis(trimethylsiloxy)pyrimidine is a quaternary salt
which readily loses a trimethylsilyl halide to give the N(1)-substituted 4-(trimethylsiloxy)pyrimidin-2(1H)-one.
Hydrolysis of the latter leads to the required N(1)-substituted derivative of uracil.
In the conditions of the silyl modification of the Gilbert–Johnson reaction α-halo ethers readily alkylate
uracil in high yields even at room temperature in aprotic solvents of low polarity [1-3, 7].
The use of less reactive alkyl halides as alkylating agents has been studied considerably less. For
example, N(1)-substituted derivatives of uracil have been obtained by the condensation of
2,4-bis(trimethylsiloxy)pyrimidine with ethyl monobromoacetate and α-bromopropionate on boiling in
dichloroethane in yields from 41 to 60% [8]. The reaction of 5-methyl-2,4-bis(trimethylsiloxy)pyrimidine with
an excess of 1,4-dichlorobutane in methylene chloride at room temperature gave 1-(4-chloro-2-butyl)thymine in
47% yield [9].
The use of alkyl halides with medium reactivity has received still less attention. It is known that the
reaction 2,4-bis(trimethylsiloxy)-5-methylpyrimidine with an excess of 1,3-dibromopropane or
1,6-dibromohexane at room temperature for 10 or 34 days gave 1-(3-bromopropyl)- and
1-(6-bromohexyl)thymine in 82 and 88 % yields [10].
Alkylation of uracil with alkyl halides of low reactivity, such as 2-chloroethoxyethyl acetate and
2-chloroethyl acetate, was carried out by heating in a polar solvent in the presence of a base, for example
potassium carbonate or sodium hydride [11, 12]. The drawback of this method is the formation of a mixture of
_______
* cf E. Ya. Lukevics and A. E. Zablotskaya. The Silyl Method for the Synthesis of Nucleosides [in Russian],
Zinatne, Riga, 1985, 440 p. (Editor's note).
__________________________________________________________________________________________
Pharmacological Research Institute, Volgograd State Medicinal University, Volgograd 400131, Russia;
e-mail: m-novikov@vlink.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, 1071-1075, July,
2005. Original article submitted February 26, 2003.
0009-3122/05/4107-0905©2005 Springer Science+Business Media, Inc.
905

N(1)-mono- and N(1),N(3)-dialkylated uracil which are usually separated by preparative chromatography. We
previously obtained 1-[2-(phenoxy)ethyl] derivatives of uracil, thymine, 6-methyluracil [7], and
5-(arylamino)uracil [13] by this method.
The objective of the present work was the adaptation of the silyl method for the synthesis of
1-[2-(phenoxy)ethyl] derivatives of uracil, while excluding the formation of the 1,3-disubstituted compounds as
side
products.
We
have
observed
that
heating
equimolar
amounts
of
5-substituted
2,4-bis(trimethylsiloxy)pyrimidines with 1-bromo-2-(phenoxy)ethanes 1-5 at 180-185°C for 3 h gave the
corresponding 1-[2-(phenoxy)ethyl]uracils in yields of 55-74%, while the 1,3-disubstituted products were not
observed.
Me3Si
O
R1
N
180–185 oC
R2
+
Me3Si
Br
O
N
O
1–5
O
N
R1
HN
O
O
R2
6–18
6, 9, 12, 15, 17 R1 = H; 7, 10, 13 R1 = Ме; 8, 11, 14, 16, 18 R1 = Br; 1, 6-8 R2 = H;
2, 9-11 R2 = 4-Ме; 3, 12-14 R2 = 4-Cl; 4, 15, 16 R2 = 3,4-Ме2; 5, 17, 18 R2 = 2,4-Cl2
Note that, on the one hand, a decrease in the reaction time led to a considerable decrease in the yield of
the required product. For example, the yield of 1-[2-(phenoxy)ethyl]uracil (6) obtained on heating for 3 h was
67%, while it was 37% on heating for 1.5 h. On the other hand the yield of compound 6 also decreased to 59%
on prolonging the heating (5 h).
In
a
study of the effect of the solvent we observed that the alkylation of
2,4-bis(trimethylsiloxy)pyrimidine with 1-bromo-2-(phenoxy)ethane (1) in boiling 1,2-dichloroethane occurred
slowly and the yield of compound 6 was only 16% after 24 h. Replacement of 1,2-dichloroethane by anhydrous
acetonitrile, which has approximately the same boiling point but a considerably higher dielectric permeability,
gave only trace amounts of compound 6.
It was also observed that the steric bulk of the substituent at position
6
in the
2,4-bis(trimethylsiloxy)pyrimidine had a considerable effect on the reaction. For example, heating
2,4-bis(trimethylsiloxy)-6-methylpyrimidine with compound 1 at 180-185°C for 6 h gave a complex mixture of
alkylation products, while the reaction with 2,4-bis(trimethylsiloxy)quinazoline did not occur at all under these
conditions.
1
The structure of the compounds synthesized 6-18 was confirmed by H NMR spectroscopy, their purity
and individuality were demonstrated by TLC, and their composition by elemental analysis.
We have developed a modification of the Gilbert–Johnson reaction which permits a considerable
broadening of the range of use of the method and the preparation of sufficiently high yields of
1-[2-(phenoxy)ethyl] derivatives of uracil which are potentially biologically active compounds.
906

TABLE 1. Characteristics of the Compounds Synthesized
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Yield,
%
mp, °С
Rf*
С
Н
N
6
C12H12N2O3
62.28
62.06
63.12
63.40
46.54
46.32
63.59
63.40
64.76
64.60
48.26
48.02
53.87
54.05
55.68
55.62
41.90
41.71
64.21
64.60
49.80
49.57
47.93
47.86
5.33
5.21
5.55
5.73
3.66
3.56
5.90
5.73
6.20
6.20
4.10
4.03
4.10
4.16
4.40
4.67
3.23
2.92
6.08
6.20
4.64
4.46
3.40
3.35
11.89
12.06
11.14
11.38
9.21
9.00
11.01
11.38
10.59
10.76
8.43
8.62
10.77
10.50
9.95
9.98
8.00
8.11
10.80
10.76
8.41
8.26
9.40
9.30
156-158
193-195
203-205
150-152
196-197
193-195
219-221
207-209
220-222
168-170
192-195
207-209
203-205
0.15
0.21
0.44
0.19
0.37
0.48
0.11
0.16
0.28
0.20
0.45
0.10
0.24
67
69
71
68
70
69
74
68
70
55
64
67
65
7
C13H14N2O3
8
C12H11BrN2O3
C13H14N2O3
9
10
11
12
13
14
15
16
17
18
C14H16N2O3
C13H13BrN2O3
C12H11ClN2O3
C13H13ClN2O3
C12H10BrClN2O3
C14H16N2O3
C14H15BrN2O3
C12H10Cl2N2O3
C12H9BrCl2N2O3
38.28
37.93
2.55
2.39
7.50
7.37
_______
* 1:1 ethyl acetate–chloroform.
EXPERIMENTAL
1H NMR spectra were recorded with Bruker DRX500 (500 MHz) and Tesla BS-567A (100 MHz)
spectrometers in 1:1 DMSO-d6–acetone-d6 solutions with TMS as internal standard. The spectra were interpreted
using licensed ACD/HNMR Predictor 3.0 programs (Advanced Chemistry Development, Canada). TLC was
carried out on Silufol UV-254 plates, developed with iodine vapor. Melting points were determined in glass
capillaries with a Mel-Temp 3.0 apparatus (Laboratory Devices Inc., USA).
1-[2-(Phenoxy)ethyl]uracil (6). 1-Bromo-2-(phenoxy)ethane (1) (3.6 g, 17.91 mmol) was added at
~20°C to 2,4-bis(trimethylsiloxy)pyrimidine, obtained by boiling uracil (2.9 g, 17.87 mmol) in HMDS (50 ml) in
the presence of NH4Cl (0.3 g), and the mixture was heated for 3 h at 180-185°C in the absence of moist air. The
reaction mixture was cooled to room temperature, dissolved in ethyl acetate (30 ml), and treated with ethanol (10
ml). The precipitate was recrystallized twice from ethanol to give compound 6 (2.8 g, 67%) as a white finely
crystalline substance. 1H NMR spectrum, δ, ppm (J, Hz): 3.79-4.37 (4H, m, CH2CH2); 5.53 (1H, d, J = 8, H-5);
6.59-7.27 (6H, m, C6H5).
Compounds 7-18 were prepared analogously.
1-[2-(Phenoxy)ethyl]thymine (7). 1H NMR spectrum, δ, ppm (J, Hz): 1.74 (3H, s, CH3); 3.98 (2H, t, J =
7, CH2); 4.12 (2H, t, J = 7, CH2); 6.60-7.29 (5H, m, C6H5); 7.36 (1H, s, H-6).
1
5-Bromo-1-[2-(phenoxy)ethyl]uracil (8). H NMR spectrum, δ, ppm (J, Hz): 3.98-4.20 (4H, m,
CH2CH2); 6.77-7.30 (5H, m, C6H5); 8.06 (1H, s, H-6); 11.48 (1H, br. s, NH).
907

1
1-[2-(4-Methylphenoxy)ethyl]uracil (9). H NMR spectrum, δ, ppm (J, Hz): 2.19 (3H, s, CH3); 4.05
(2H, J = 6, N–CH2); 4.12 (2H, J = 6, CH2O); 5.45 (1H, dd, J = 8 and 2, H-5); 6.69-7.05 (4H, m, C6H4); 7.49 (1H,
d, J = 8, H-6); 11.02 (1H, br. s, NH).
1-[2-(4-Methylphenoxy)ethyl]thymine (10). 1H NMR spectrum, δ, ppm (J, Hz): 1.71 (3H, s, CH3); 2.15
(3H, s, CH3); 3.89-4.22 (4H, m, CH2CH2); 6.66-7.05 (4H, m, C6H4); 7.35 (1H, s, H-6); 11.17 (1H, br. s, NH).
1
5-Bromo-1-[2-(4-methylphenoxy)ethyl]uracil (11). H NMR spectrum, δ, ppm (J, Hz): 2.26 (3H, s,
CH3); 4.08 (2H, t, J = 6, N–CH2); 4.14 (2H, t, J = 6, CH2O); 6.74-7.06 (4H, m, C6H4); 8.02 (1H, s, H-6); 11.60
(1H, br. s, NH).
1
1-[2-(4-Chlorophenoxy)ethyl]uracil (12). H NMR spectrum, δ, ppm (J, Hz): 4.06 (2H, t, J = 6,
N–CH2); 4.18 (2H, t, J = 6, CH2O); 5.46 (1H, dd, J = 8 and 2, H-5); 6.89-7.30 (4H, m, C6H4); 7.53 (1H, d, J = 8,
H-6); 11.07 (1H, br. s, NH).
1-[2-(4-Chlorophenoxy)ethyl]thymine (13). 1H NMR spectrum, δ, ppm (J, Hz): 1.81 (3H, s, CH3); 4.02
(2H, t, J = 6, N–CH2); 4.16 (2H, t, J = 6, CH2O); 6.88-7.25 (4H, m, C6H4); 7.46 (1H, s, H-6); 11.04 (1H, br. s,
NH).
1
5-Bromo-1-[2-(4-chlorophenoxy)ethyl]uracil (14): H NMR spectrum, δ, ppm (J, Hz): 4.09 (2H, t,
J = 6, N–CH2); 4.19 (2H, t, J = 6, CH2O); 6.89-7.25 (4H, m, C6H4); 8.05 (1H, s, H-6); 11.63 (1H, br. s, NH).
1
1-[2-(3,4-Dimethylphenoxy)ethyl]uracil (15): H NMR spectrum, δ, ppm (J, Hz): 2.17 (3H, s, CH3);
2.20 (3H, s, CH3); 4.04 (2H, t, J = 6, N–CH2); 4.12 (2H, t, J = 6, CH2O); 5.46 (1H, dd, J = 8 and 2, H-5); 6.58
(1H, m, H-2'); 6.67 (1H, m, H-6'); 6.96 (1H, m, H-3'); 7.50 (1H, d, J = 8, H-6); 11.01 (1H, br. s, NH).
1
5-Bromo-1-[2-(3,4-dimethylphenoxy)ethyl]uracil (16): H NMR spectrum, δ, ppm (J, Hz): 2.21 (3H,
s, CH3); 2.24 (3H, s, CH3); 4.08 (2H, t, J = 6, N–CH2); 4.14 (2H, t, J = 6, CH2O); 6.61 (1H, m, H-2'); 6.69 (1H,
m, H-6'); 6.94 (1H, m, H-3'); 8.06 (1H, H-6); 11.52 (1H, br. s, NH).
1
1-[2-(2,4-Dichlorophenoxy)ethyl]uracil (17): H NMR spectrum, δ, ppm (J, Hz): 4.08 (2H, t, J = 6,
N–CH2); 4.13 (2H, t, J = 6, CH2O); 5.44 (1H, dd, J = 8 and 2, H-5); 6.92-7.33 (3H, m, C6H3); 7.49 (1H, d, J = 8,
H-6); 11.21 (1H, br. s, NH).
5-Bromo-1-[2-(2,4-dichlorophenoxy)ethyl]uracil (18): 1H NMR spectrum, δ, ppm (J, Hz): 4.11 (2H, t,
J = 6, N–CH2); 4.15 (2H, t, J = 6, CH2O); 6.98-7.30 (3H, m, C6H3); 8.10 (1H,s, H-6); 11.68 (1H, br. s, NH).
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