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Y. M. Loksha et al.
Arch. Pharm. Chem. Life Sci. 2009, 342, 501–506
(0.6 g, 2 mmol) in dry chloroform (20 mL) and the solution was
refluxed for 3 h. The reaction mixture was cooled to r.t. and
quenched with 5% aq. sodium bicarbonate solution (2 mL).
Water (10 mL) was added and the two layers were separated. The
chloroform layer was dried using sodium sulfate and evaporated
under reduced pressure. The residual material was chromato-
graphed on a silica gel column using petroleum ether / ether
(2 : 1, v/v) as eluent to give two compounds 3 and 4.
mixture at r.t. and stirred for 3 h. The reaction was quenched by
addition of 5% aq. sodium bicarbonate solution (3 mL). Water
(10 mL) and methylene chloride (10 mL) were added to the reac-
tion mixture. The two layers were separated and the organic
layer was dried using sodium sulfate. The solvent was removed
under reduced pressure and the residual material was purified
by silica gel column chromatography using ethyl acetate /
methylene chloride (1 : 1, v / v) as eluent to afford 200 mg of
1
compound 6, yield: 61%; m.p.: 123–1258C; H-NMR (CDCl3) d
[ppm]: 0.79 (t, J = 7.1 Hz, 3H, CH3CH2), 0.97 (t, J = 7.5 Hz, 3H,
CH3CH2O), 1.94–2.01 (m, 1H, CH3-HCH), 2.24–2.31 (m, 1H, CH3-
HCH), 3.29-3.45 (m, J = 7.5 Hz, 2H, CH3-CH2-O), 4.82 (d, J = 10.1 Hz,
1H, N-HCH-O), 5.56 (d, J = 10.1 Hz, 1H, N-HCH-O), 7.72 (t, J = 7.8 Hz,
1H, Harom), 8.0 (dt, J = 7.8, 1.4 Hz, 1H, Harom), 8.16 (dt, J = 8.1, 1.2 Hz,
1H, Harom), 8.25 (t, J = 1.4 Hz, 1H, Harom), 9.57 (s, 1H, NH); 13C-NMR
(CDCl3) d [ppm]: 13.22 (CH3CH2), 14.14 (CH3CH2O), 19.15 (CH3CH2),
64.33 (CH3CH2O), 72.97 (NCH2O), 117.21 (C5), 115.45 (CN), 113.70,
129.98, 132.90, 133.21, 136.17, 137.46 (Carom), 144.34 (C4), 150.42
(C2), 162.54 (C6), 187.87 (C=O); EI MS m/z: 327 [M+] (11%), 59
(100%). Anal. calcd. for C17H17N3O4 (327.33): C, 62.38; H, 5.23; N,
12.84. Found: C, 62.46; H, 5.28; N, 12.65.
3-[(5-Ethyl-6-methoxy-2-oxo-2,3-dihydropyrimidin-4-
yl)carbonyl]benzonitrile 3
Yield: 35%; m.p.: 223–2258C; 1H-NMR (CDCl3) d [ppm]: 0.91 (t, J =
7.1 Hz, 3H, CH3CH2), 2.15 (q, J = 7.1 Hz, 2H, CH3CH2), 3.86 (s, 3H,
OCH3), 5.31 (bs, 1H, NH), 7.78 (t, J = 8.0 Hz, 1H, Harom), 8.16-8.19
(m, 2H, Harom), 8.28 (s, 1H, Harom); 13C-NMR (CDCl3) d [ppm]: 14.57
(CH3CH2), 17.68 (CH3CH2), 53.31 (OCH3), 105.07 (C5), 117.83 (CN),
112.12, 130.28, 133.32, 133.84, 135.82, 137.37 (Carom), 155.87 (C4),
161.42 (C2), 169.50 (C6), 190.91 (C=O); EI MS m/z: 283 [M+] (59%),
254 (100%); HRMS (MALDI) m/z: 284.1029 (C15H14N3O3 [M + H+]),
requires: 284.1030.
3-[(5-Ethyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-
yl)carbonyl]benzonitrile 4
Synthesis of 3-{[6-(3-cyanobenzoyl)-5-ethyl-2,4-dioxo-
3,4-dihydropyrimidin-1(2H)-yl]methyl}-benzonitrile 7
Yield: 37%; m.p.: 226–2288C; 1H-NMR (DMSO-d6) d [ppm]: 0.87 (t, J
= 7.2 Hz, 3H, CH3CH2), 2.01 (q, J = 7.2 Hz, 2H, CH3CH2), 7.84 (t, J =
7.8 Hz, 1H, Harom), 8.24 (dt, J = 7.8, 1.4 Hz, 2H, Harom), 8.30 (dt, J =
7.8, 1.4 Hz, 1H, Harom), 8.56 (t, J = 1.5 Hz, 1H, Harom), 11.08, 11.32
(2s, 2H, 2 NH); 13C-NMR (DMSO-d6) d [ppm]: 13.58 (CH3CH2), 17.96
(CH3CH2), 112.60 (C5), 111.76, 130.57, 133.57, 133.67, 134.99,
138.26 (Carom), 144.05 (C4), 150.39 (C2), 164.39 (C6), 188.73 (C=O);
HRMS (MALDI) m/z: 292.0688 (C14H11N3O3 [M + H+]), requires:
292.0693.
To a stirred solution of compound 4 (80 mg, 0.3 mmol) dry
methylene chloride (10 mL) under nitrogen atmosphere, N,O-
bis(trimethylsilyl)acetamide (BSA) (0.25 mL, 1 mmol) was added.
After complete silylation (clear solution, after 10 min), 3-cyano-
benzyl bromide (86 mg, 0.44 mmol) was added to the mixture
and it was refluxed for 16 h. The reaction mixture was cooled to
r.t. and the solvent was removed under reduced pressure. The
residual material was purified by silica gel column chromatogra-
phy using EtOAc / CH2Cl2 (1 : 1, v / v) as eluent to afford 60 mg of
1
compound 7, yield: 52%; m.p.: 250-2528C; H-NMR (DMSO-d6) d
Synthesis of 3-{[3-(ethoxymethyl)-5-ethyl-6-methoxy-2-
[ppm]: 0.83 (t, J = 7.2 Hz, 3H, CH3CH2), 1.86, 2.00 (2bs, 2H,
CH3CH2), 4.64, 4.87 (2bs, 2H, CH2Ar), 7.30–7.39 (m, 2H, Harom),
7.54–760 (m, 2H, Harom), 7.68 (t, J = 7.8 Hz, 1H, Harom), 8.10 (d, J =
7.8 Hz, 1H, Harom), 8.23 (d, J = 7.8 Hz, 1H, Harom), 8.44 (s, 1H, Harom);
13C-NMR (DMSO-d6) d [ppm]: 13.09 (CH3CH2), 18.68 (CH3CH2), 47.01
(CH2Ar), 113.32 (C5), 117.25 (CN), 118.31 (CN), 111.10, 112.38,
129.12, 130.31, 130.65, 130.92, 131.72, 133.09, 134.27, 134.59,
137.59, 138.46 (Carom), 145.15 (C6), 151.01 (C2), 163.065 (C4),
188.59 (COAr); EI MS m/z: 384 [M+] (27%), 116 (100%). Anal. calcd.
for C22H16N4O3 . 0.2 H2O (388.00): C, 68.10; H, 4.26; N, 14.44.
Found: C, 68.10; H, 4.17; N, 14.08.
oxo-2,3-dihydropyrimidin-4-yl]carbonyl}-benzonitrile 5
Triethylamine (0.06 mL, 0.42 mmol) was added to a stirred solu-
tion of compound 3 (100 mg, 0.35 mmol) and ethoxymethyl
chloride (0.04 mL, 0.42 mmol) in dry methylene chloride (10 mL)
at r.t. The reaction mixture was stirred for 3 h, the solvent was
evaporated under reduced pressure and the residual material
was purified by silica gel column chromatography using CH2Cl2
as eluent to furnish 66 mg of compound 5, yield 55%; m.p.: 70–
728C;1H-NMR (CDCl3) d [ppm]: 1.12 (t, J = 7.4 Hz, 3H, CH3CH2), 1.25
(t, J = 7.2 Hz, 3H, CH3CH2), 2.52 (q, J = 7.4 Hz, 2H, CH3CH2), 3.80 (q,
J = 7.2 Hz, 2H, CH3CH2), 4.09 (s, 3H, OCH3), 5.54 (s, 2H, NCH2O),
7.61 (t, J = 7.5 Hz, 1H, Harom), 7.87 (dt, J = 7.8, 1.5 Hz, Harom), 8.17-
8.21 (m, 2H, Harom); 13C-NMR (CDCl3) d [ppm]: 14.08 (CH3CH2),
15.02 (CH3CH2O), 18.28 (CH3CH2), 54.60 (OCH3), 65.70 (CH3CH2O),
91.79 (NCH2O), 116.98 (C5), 117.75 (CN), 112.95, 129.46, 133.97,
134.15, 136.19, 136.43 (Carom), 160.18 (C2), 161.25 (C4), 170.84
(C6), 190.93 (C=O); HRMS (MALDI) m/z: 364.1258 (C18H19NaN3O4 [M
+ Na+])], requires: 364.1268.
Synthesis of 3-[(5-ethyl-2,6-dimethoxypyrimidin-4-
yl)(hydroxy)methyl]benzonitrile 8
Under ice cooling bath, sodium borohydride (170 mg, 4.5 mmol)
was added portionwise to a stirred solution of compound 2
(1.2 g, 4 mmol) in methanol (20 mL). The reaction mixture was
left to reach r.t. gradually with stirring for 1 h, then acetic acid
(1 mL) was added followed by addition of water (40 mL) and
ether (50 mL). The two layers were separated and the ether layer
was dried (MgSO4) and evaporated under reduced pressure. The
oily residual material was 0.8 g of the pure compound 8, yield
67%; yellow oil; 1H-NMR (CDCl3) d [ppm]: 0.83 (t, J = 7.5 Hz, 3H,
CH3CH2), 2.31-2.50 (m, 2H, CH3CH2), 4.02, 4.05 (2s, 6H, 2OCH3),
5.15 (d, J = 7.5 Hz, 1H, OH), 5.76 (d, J = 7.5 Hz, 1H, CH), 7.41–7.60
(m, 4H, Harom); 13C-NMR (CDCl3) d [ppm]: 12.61 (CH3CH2), 17.43
(CH3CH2), 54.38, 54.79 (2 OCH3), 70.47 (CH), 118.47 (CN), 113.18
Synthesis of 3-{[3-(ethoxymethyl)-5-ethyl-2,6-dioxo-
1,2,3,6-tetrahydropyrimidin-4-yl]carbonyl}-benzonitrile 6
Compound 4 (0.29 g, 1 mmol) was stirred in dry methylene
chloride (15 mL) under nitrogen atmosphere, and N,O-bis(trime-
thylsilyl)acetamide (BSA) (0.87 mL, 3.5 mmol) was added. After
complete silylation (clear solution, after 10 min), ethoxymethyl
chloride (0.14 mL, 1.5 mmol) was added dropwise to the reaction
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