216
F. A. El-Essawy, N. R. El-Brollosy, E. B. Pedersen and C. Nielsen
Vol. 40
3-[(2-Acetoxyethoxy)methyl]-5-cyano-6-cyclohexyluracil (5d).
General Procedure for the Preparation of Compounds (9a,b).
This compound was obtained as colorless crystals, yield 0.1 g
(33%); mp 159-161°; H nmr (deuteriochloroform): δ 1.31-1.91
To a stirred solution of 1b (0.22 g, 1 mmole) in dry N,N-
dimethylformamide (10 ml), 0.04 g (1mmole) of sodium hydride
(60% dispersion in mineral oil) was added. After evolution of
hydrogen has completed (1 hour), the appropriate 2,2-dimethyl-
1,3-dioxolane-4-yl alkyl p-toluenesulfonate (8a,b, 1.1 mmoles)
was added in one portion, and the reaction mixture was stirred for
additional 8-10 hours at 100°. The reaction mixture was cooled to
room temperature, and the solvent was evaporated in vacuo. The
compounds were purified by silica gel column chromatography
with chloroform:ethyl acetate (95:5, v/v).
1
(m, 10 H, 5 x CH ), 2.06 (s, 3 H, CH ), 2.94 (m, 1 H, CH), 3.84
2
3
(t, 2 H, J = 4.9 Hz, CH ), 4.18 (t, 2 H, J = 4.9 Hz, CH ), 5.43 (s, 2
2
2
13
H, CH ), 10.32 (brs, 1 H, NH); C nmr (deuteriochloroform): δ
2
20.80 (CH ), 25.01, 25.43, 29.47, 42.29 (C
), 63.11
3
cylclohexyl
(CH ), 68.79 (CH ), 71.06 (CH ), 87.76 (C-5), 112.70 (CN),
2
2
2
151.26 (C-2), 159.85 (C-4), 167.67 (C-6), 170.84 (CO). HRms
+
(MALDI): m/z 358 (M + Na ): Anal. Calcd. for C H N NaO :
16 21
3
5
358.1373. Found: 358.1380.
1,3-Bis(ethoxymethyl)-5-cyano-6-(2-phenylethyl)uracil (4b).
5-Cyano-6-cyclohexyl-3-((S)-2,2-dimethyl-1,3-dioxolan-4-
ylmethyl)uracil (9a).
This compound was obtained as colorless crystals, yield 0.15 g
1
(42%); mp 124-126°; H nmr (deuteriochloroform): δ 1.19, 1.22 (2
This compound was obtained as colorless crystals, yield 0.2 g
1
x t, 6 H, J = 7.0 Hz, 2 x CH ), 3.04-3.09 (m, 2 H, CH ), 3.17-3.23
(17%); mp 123-125°; H nmr (deuteriochloroform): δ 1.21 (s, 3
3
2
(m, 2 H, CH ), 3.64, 3.65 (2 x q, 4 H, J = 7.0 Hz, 2 x CH ), 5.35 (s,
H, CH ), 1.47 (s, 3 H, CH ), 1.23-1.91 (m, 10 H, 5 x CH ), 2.94-
2
2
3
3
2
13
2 H, CH ), 5.42 (s, 2 H, CH ), 7.24-7.37 (m, 5 H, H ): C nmr
3.05 (m, 1 H, CH), 3.79 (dd, 1 H, J = 5.3, 8.9 Hz, CH ), 3.88 (dd,
2
2
arom
2
(deuteriochloroform): δ 14.95, 15.08 (2 x CH ), 34.24 (CH ),
1 H, J = 4.9, 12.9 Hz, CH ), 4.06 (dd, 1 H, J = 6.4, 8.8 Hz, CH ),
3
2
2
2
34.90 (CH ), 65.90, 66.34 (2 x CH ), 71.46 (CH ), 74.43 (CH ),
4.24 (dd, 1 H, J = 7.3, 12.9 Hz, CH ), 4.42-4.51 (m, 1 H, CH),
10.55 (brs, 1 H, NH); C nmr (deuteriochloroform): δ 25.08,
2
2
2
2
2
13
90.93 (C-5), 113.17 (CN), 127.22, 128.31, 128.95, 138.37 (Ar),
+.
150.88 (C-2), 158.77 (C-4), 165.40 (C-6); EI ms: m/z 357 (M ).
26.65, 29.47, 42.21 (C
), 25.29 (CH ), 25.45 (CH ), 44.23
cyclohexyl
3 3
(CH ), 67.46 (CH ), 72.46 (CH), 87.85 (C-5), 109.87 (C(CH ) ),
112.87 (CN), 151.78 (C-2), 159.70 (C-4), 166.90 (C-6).
2
2
3 2
1,3-Bis(ethoxymethyl)-5-cyano-6-cyclohexyluracil (6b).
This compound was obtained as colorless crystals, yield 0.11 g
5-Cyano-6-cyclohexyl-3-[2-((S)-2,2-dimethyl-1,3-dioxolan-4-
yl)ethyl]uracil (9b).
1
(33%); mp 119-120°; H nmr (deuteriochloroform): δ 1.19, 1.20
(2 x t, 6 H, J = 7.0 Hz, 2 x CH ), 1.33-2.26 (m, 10 H, 5 x CH ),
3
2
3.01-3.06 (m, 1 H, CH), 3.62, 3.64 (2 x q, 4 H, J = 7.0 Hz, 2 x
This compound was obtained as colorless crystals, yield 0.1 g
(66%); mp 189-191°; H nmr (deuteriochloroform): δ 1.30 (s, 3
13
1
CH ), 5.41 (s, 2 H, CH ), 5.49 (s, 2 H, CH ); C nmr (deuteri-
2
2
2
ochloroform): δ 14.94, 15.04 (2 x CH ), 24.75, 26.10, 28.89,
H, CH ), 1.36 (s, 3 H, CH ), 1.30-1.99 (m, 10 H, 5 x CH ), 2.90-
3
3
3
2
40.92 (C
), 65.32, 66.33 (2 x CH ), 71.49, 74.13 (2 x
3.01 (m, 1 H, CH
), 3.53-3.58 (m, 2 H, CH ), 3.93-4.27
cyclohexyl
2
cyclohexyl
2
13
CH ), 87.85 (C-5), 113.76 (CN), 150.95 (C-2), 159.59 (C-4),
(m, 5 H, CH, CH CH ), 10.68 (brs, 1 H, NH); C nmr (deuteri-
2
2
2
+
170.23 (C-6). HRms (MALDI): m/z 358 (M + Na ): Anal. Calcd.
ochloroform): δ 25.15, 26.81, 29.46, 42.15 (C
), 25.44,
cyclohexyl
for C H N NaO : 358.1737. Found: 358.1750.
25.45 (2 x CH ), 31.02 (CH ), 38.72 (CH ), 69.03 (CH ), 73.94
17 25
3
4
3
2
2
2
(CH), 87.68 (C-5), 109.05 (C (CH ) ), 112.97 (CN), 151.68 (C-
2), 159.74 (C-4), 166.72 (C-6).
3 2
1, 3-Bis[(2-acetoxyethoxy)methyl]-5-cyano-6-(2-
phenylethyl)uracil (4d).
General Procedure for the Deprotection of Compounds (9a,b).
This compound was obtained as an viscous oil, yield 0.2 g
1
(45%); H nmr (deuteriochloroform): δ 2.00 (s, 3 H, CH ), 2.06
Compound 9a or 9b (1mmole) was dissolved in 80% aqueous
acetic acid (10 ml) and the solution was stirred overnight at room
temperature. The volatiles were evaporated in vacuo and the
residue was coevaporated with water (3 x 5 ml), and finally with
ethanol (3 x 5 ml). The compounds 10a,b were purified by silica
gel column chromatography with chloroform:methanol (95:5, v/v).
3
(s, 3 H, CH ), 3.05-3.11 (m, 2 H, CH ), 3.16-3.22 (m, 2 H, CH ),
3
2
2
3.85-3.89 (m, 4 H, OCH CH O), 4.18-4.23 (m, 4 H,
2
2
OCH CH O), 5.42 (s, 2 H, CH ), 5.46 (s, 2 H, CH ), 7.26-7.37
2
2
2
2
13
(m, 5 H, H
); C nmr (deuteriochloroform): δ 20.26, 20.74 (2
arom
x CH ), 34.23, 34.63 (2 x CH ), 90.94 (C-5), 112.96 (CN),
3
2
127.17, 128.21, 128.88, 138.19 (Ar), 150.48 (C-2), 158.62 (C-4),
5-Cyano-6-cyclohexyl-3-((S)-2,3-dihydroxypropyl)uracil (10a).
165.36 (C-6), 170.54, 170.73 (2 x COCH ). HRms (MALDI):
3
+
This compound was obtained as a colorless viscous oil, yield
m/z 496 (M + Na ): Anal. Calcd. for C H N NaO : 496.1690.
23 27
3
8
1
61 mg (60%); H nmr (DMSO-d ): δ 1.17-1.91 (m, 10 H, 5 x
Found: 496.1672.
6
CH ), 2.67-2.72 (m, 1 H, CH), 3.67-3.91 (m, 5 H, CH, 2 x CH ),
2
2
5-Cyano-6-cyclohexyl-3-(2-hydroxyethoxymethyl)uracil (7).
13
4.78 (brs, 2 H, 2 x OH); C nmr (DMSO-d ): δ 24.73, 25.40,
6
Compound 5d (60 mg, 0.2 mmole) was dissolved in 50%
methanolic ammonia (10 ml) and the mixture was stirred for 5
hours at 50-60°. The solvent was evaporated in vacuo and the
residue was purified by silica gel column chromatography with
28,64, 42.50 (C
(CH), 83.89 (C-5), 115.37 (CN), 151.69 (C-2), 161.41 (C-4),
169.19 (C-6). HRms (MALDI): m/z 316 (M + Na ): Anal. Calcd.
), 43.66 (CH ), 64.16 (CH ), 68.18
cyclohexyl
2 2
+
for C H N O Na: 316.1268. Found: 316.1264.
14 19
3 4
chloroform:methanol (95:5, v/v) as the eluent to give 7 (30 mg,
5-Cyano-6-cyclohexyl-3-((S)-3,4-dihydroxybutyl)uracil (10b).
1
60%) as a colorless viscous oil; H nmr (DMSO-d ): δ 1.19-1.81
6
(m, 10 H, 5 x CH ), 2.64-2.68 (m, 1 H, CH), 3.41-3.47 (m, 2 H,
This compound was obtained as a colorless viscous oil, yield
2
1
CH ), 3.58-3.62 (m, 2 H, CH ), 4.62 (br s, 1 H, OH), 5.11 (s, 2 H,
60 mg (86%); H nmr (DMSO-d ): δ 1.18-1.81(m, 10 H, 5 x
2
2
6
13
CH ); C nmr (DMSO-d ): δ 24.64, 25.31, 28.39, 42.50
CH ), 2.68-2.72 (m, 1 H, CH), 3.21-3.45 (m, 3 H, CH, CH ),
2
6
2
2
(C
), 60.06 (CH ), 70.19 (CH ),71.58 (NCH O), 84.39
3.70-3.79, 3.89-3.98 (2 x m, 2 H, CH ), 4.53 (brs, 2 H, 2 x OH);
cyclohexyl
2
2
2
2
13
(C-5), 114.77 (CN), 150.78 (C-2), 160.91 (C-4), 169.38 (C-6).
C nmr (DMSO-d ): δ 24.14, 24.88, 27.86, 41.75 (C
),
6
cyclohexyl