C. Mugnaini et al. / European Journal of Medicinal Chemistry 42 (2007) 256e262
261
[M þ 1]þ. Anal Calcd for C11H17N3OS: C, 55.20; H, 7.16; N,
Mp 201e202 ꢀC (dec.). 1H NMR (CD3OD): d 3.90 (t,
J ¼ 6.7 Hz, 2H), 3.03 (t, J ¼ 6.7 Hz, 2H), 2.55 (s, 3H). MS
(ESI): m/z 313 [M þ 1]þ. Anal Calcd for C7H9IN2O2S: C,
26.94; H, 2.91; N, 8.97. Found: C, 26.83; H, 2.92; N, 8.93.
17.56. Found: C, 55.13; H, 7.34; N, 17.42.
4.2.1.2. 2-[6-(Diallylamino)-2-(methylthio)-4-pyrimidinyl]-1-
ethanol (1c). Purification on preparative TLC (eluent:
CHCl3/MeOH, 9/1). Colourless oil (56%). 1H NMR
(CDCl3): d 5.90 (s, 1H), 5.87e5.71 (m, 2H), 5.17e5.07 (m,
4H), 4.23e4.02 (m, 4H), 3.89 (t, J ¼ 5.2 Hz, 2H), 2.71 (t,
J ¼ 5.2 Hz, 2H), 2.44 (s, 3H). MS (ESI): m/z 266 [M þ 1]þ.
Anal Calcd for C13H19N3OS: C, 58.84; H, 7.22; N, 15.83.
Found: C, 58.66; H, 7.31; N, 15.94.
4.3. General procedure for the preparation of 6aec
To a solution of the appropriate alcohol 5 (0.23 mmol) in
dry CH2Cl2 (10 mL) TsCl (51 mg, 0.27 mmol) and DMAP
(33 mg, 0.27 mmol) were added and the reaction mixture
was stirred overnight at room temperature. The organic solu-
tion was washed with 2 N HCl, brine and dried over anhydrous
Na2SO4. After filtration and evaporation of the solvent, the
residue was purified by column chromatography (eluent:
CHCl3/MeOH, 95/5) giving the corresponding tosylate 6aec.
4.2.1.3. 2-[2-(Methylthio)-6-(1,3-thiazolan-3-yl)-4-pyrimidinyl]-
1-ethanol (1n). Purification by column chromatography (elu-
ent: CHCl3/MeOH, 9/1).
Yellow solid (75%). Mp 77e79 ꢀC. 1H NMR (CDCl3):
d 5.91 (s, 1H), 4.60 (s, 2H), 3.92 (t, J ¼ 5.4 Hz, 2H), 3.76 (t,
J ¼ 6.1 Hz, 2H), 3.10 (t, J ¼ 6.1 Hz, 2H), 2.75 (t, J ¼ 5.4 Hz,
2H), 2.46 (s, 3H). MS (ESI): m/z 258 [M þ 1]þ. Anal Calcd
for C10H15N3OS2: C, 46.67; H, 5.87; N, 16.33. Found: C,
46.54; H, 5.93; N, 16.42.
4.3.1. Example
4.3.1.1. 5-Chloro-6-(2-hydroxyethyl)-2-(methylthio)-4-pyrimi-
dinyl 4-methyl-1-benzenesulfonate (6a). White solid (70%).
Mp 94e96 ꢀC. 1H NMR (CDCl3): d 7.90 (d, J ¼ 8.5 Hz,
2H), 7.41 (d, J ¼ 8.5 Hz, 2H), 3.90 (t, J ¼ 6.4 Hz, 2H), 2.84
(t, J ¼ 6.4 Hz, 2H), 2.41 (s, 3H), 2.32 (s, 3H). MS (ESI):
m/z 398 [M þ Na]þ. Anal Calcd for C14H15ClN2O4S2: C,
44.86; H, 4.03; N, 7.47. Found: C, 45.03; H, 4.04; N, 7.49.
4.2.2. 5-Chloro-6-(2-hydroxyethyl)-2-(methylthio)-3,4-dihydro-
4-pyrimidinone (5a)
To a solution of 3 (100 mg, 0.54 mmol) in DMF (2 mL)
NCS (98.3 mg, 1.34 mmol) was added and the reaction
mixture was irradiated at 50 ꢀC for 15 min. The solvent was
removed and the residue was purified by column chromatogra-
phy (eluent: CHCl3/MeOH, 9/1) giving 5a (64 mg, 54%) as
4.4. General procedure for the preparation of 2aem
A solution of 6 (0.20 mmol, 1 equiv) in dry THF (8 mL)
was introduced in 13 different vessels of Buchi SyncoreÒ
1
a white solid. Mp 168e170 ꢀC. H NMR (CD3OD): d 3.91
¨
and the appropriate amines were added (0.30 mmol,
1.5 equiv). The reaction mixtures were heated overnight at re-
flux temperature at 250 rpm. The solvent was partially evapo-
rated and the reaction mixtures were cooled down to room
temperature. Each reaction mixture was diluted with CH2Cl2
(5 mL), then P-TBD (0.60 mmol, 3 equiv) was added and
the mixture was stirred for 1 h. Finally, PB-4-benzyloxyben-
zaldehyde (0.90 mmol, 4.5 equiv) was added and the reaction
mixtures were stirred for additional 24 h. The reaction mix-
tures were filtered in parallel and the scavengers were washed
twice with CH2Cl2 (5 mL) and MeOH (5 mL). After evapora-
tion of the solvents, the residues were purified by column
chromatography (eluent: CH2Cl2/MeOH, 98/2) to give the fi-
nal compounds 2aem as pure products.
(t, J ¼ 6.5 Hz, 2H), 2.96 (t, J ¼ 6.5 Hz, 2H), 2.55 (s, 3H).
MS (ESI): m/z 243 [M þ Na]þ. Anal Calcd for C7H9N2O2SCl:
C, 38.10; H, 4.11; N, 12.69. Found: C, 37.94; H, 4.12; N,
12.63.
4.2.3. 5-Bromo-6-(2-hydroxyethyl)-2-(methylthio)-3,4-dihydro-
4-pyrimidinone (5b)
To a solution of 3 (1.60 g, 8.60 mmol) in dry MeOH
(40 mL) DTBP (4.82 mL, 21.5 mmol) and NBS were added
at 0 ꢀC. After 1 h, the solvent was evaporated at reduced pres-
sure and the residue was purified by column chromatography
(eluent: CHCl3/MeOH, 9/1) giving 5b (1.58 g, 69%) as a white
solid.
Mp 167e170 ꢀC. 1H NMR (CD3OD): d 3.91 (t, J ¼ 6.5 Hz,
2H), 2.97 (t, J ¼ 6.5 Hz, 2H), 2.55 (s, 3H). MS (ESI): m/z 266
[M þ 1]þ. Anal Calcd for C7H9BrN2O2S: C, 31.71; H, 3.42;
N, 10.57. Found: C, 31.65; H, 3.42; N, 10.60.
4.4.1. Examples
4.4.1.1. 2-[5-Chloro-2-(methylthio)-6-(pentylamino)-4-pyrimi-
1
dinyl]-1-ethanol (2a). White solid (67%). Mp 64e67 ꢀC. H
4.2.4. 6-(2-Hydroxyethyl)-5-iodo-2-(methylthio)-3,4-dihydro-
4-pyrimidinone (5c)
NMR (CDCl3): d 3.92 (m, 2H), 3.50e3.44 (m, 2H), 2.87 (t,
J ¼ 5.4 Hz, 2H), 2.51 (s, 3H), 1.75e1.52 (m, 2H), 1.34e
1.27 (m, 4H), 0.91e0.85 (m, 3H). MS (ESI): m/z 290
[M þ 1]þ. Anal Calcd for C12H20N3OSCl: C, 49.73; H, 6.96;
N, 14.50. Found: C, 49.85; H, 6.83; N, 14.42.
To a solution of 3 (300 mg, 1.61 mmol) in DMF (6 mL)
a 1 M solution of ICl in CH2Cl2 (3.3 mL, 3.3 mmol) was
added and the reaction mixture was irradiated at 50 ꢀC for
15 min. After evaporation of the solvent, the residue was puri-
fied by column chromatography (eluent: CHCl3/MeOH, 9/1)
giving 5c (302 mg, 60%) as a white solid.
4.4.1.2. 2-[6-(Allylamino)-5-iodo-2-(methylthio)-4-pyrimidinyl]-
1
1-ethanol (2f). White solid (100%). Mp 74e76 ꢀC. H NMR