November 2009
Synthesis of 4-Substituted 2-(4-Methylpiperazino)pyrimidines and
Quinazoline Analogs as Serotonin 5-HT2A Receptor Ligands
1263
4-[(Cyclohexen-1-yl)ethynyl)]-2-(4-methylpiperazino)- py-
rimidine (8). This compound was obtained as an oil in 59%
yield; 1H NMR: d 1.66 (???m, 4H), 2.20 (m, 4H), 2.34 (s,
3H), 2.46 (m,4H), 3.85 (m, 4H), 6.37 (m, 1H), 6.55 (d, J ¼ 5
Hz, 1H), 8.24 ppm (d, J ¼ 5 Hz, 1H). The hydrobromide salt
had mp 242ꢁC (decomp). Anal. Calcd. for C17H22N4ꢃHBr: C,
56.20; H, 6.38; N, 15.42. Found: C, 56.08; H, 6.47; N, 15.34.
2-(4-Methylpiperazino)-4-(2-biphenyl)pyrimidine (9). This
4-(1,3-Dioxane-2-yl)-2-(4-methylpiperazino)pyrimidine (16).
This compound was obtained as an oil in 71% yield The
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1
hydrobromide salt had mp 179–180 C; H NMR (salt, deuter-
iochloroform): d 1.49 (m, 1H),2.26(m, 1H), 2.82 (s, 3H), 2.85
(m, 2H), 3.59 (m, 2H), 3.94 (m, 4H), 4.28 (m, 2H), 4.98 (m,
2H), 5.32 (s, 1H), 6.97 (d, J ¼ 5 Hz, 1H), 8.42 ppm (d, J ¼ 5
Hz, 1H). Anal. Calcd. for 2C13H20N4O2ꢃ2HBrꢃH2O: C, 44.08;
H, 6.26; N, 15.82. Found: C, 43.93; H, 6.01; N, 15.64.
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1
compound had mp 8587 C and was obtained in 86% yield; H
NMR: d 2.04 (s, 3H), 2.37 (m, 4H), 3.67–3.69 (m, 4H), 6.29
(d, J ¼ 5 Hz, 1H), 7.25 (m, 3H), 7.44 (m, 3H), 7.70 (m, 3H),
4-(3,4-Dihydro-2H-pyran-6-yl)-2-(4-methylpiperazino)-py-
rimidine (17). This compound was obtained as an oil in 80%
yield; 1H NMR: d 1.91 (m, 2H), 2.25 (m, 2H), 2.33 (s, 3H),
2.47 (m, 4H), 3.86 (m, 4H), 4.15 (m, 2H), 6.21 (m, 1H), 6.74
(d, J ¼ 5 Hz, 1H), 8.32 ppm (d, ꢁJ ¼ 5 Hz, 1H). The hydrobro-
8.09 ppm (d,
J
¼
5
Hz, 1H). Anal. Calcd. for
C21H22N4ꢃ2HBrꢃH2O: C, 49.43; H, 5.14; N, 10.98. Found: C,
49.32; H, 5.00; N, 10.57.
mide
had
mp
192–194 C.
Anal.
Calcd.
for
2-(4-Methylpiperazino)-4-(9-phenanthryl)pyrimidine (10). This
compound was obtained as an oil in 78% yield; 1H NMR: d
2.32 (s, 3H), 2.48 (m, 4H), 3.93–3.97 (m, 4H), 6.81 (d, J ¼ 5
Hz, 1H), 7.58 (m, 2H), 7.63–7.67 (m, 2H), 7.89 (m, 2H), 8.28
(d, J ¼ 8 Hz, 1H), 8.44 (d, J ¼ 5 Hz, 1Hꢁ), 8.70 ppm (m, 2H).
The hydrobromide salt had mp 195–198 C. Anal. Calcd. for
2C23H22N4ꢃ3HBrꢃ4H2O: C, 53.97; H, 5.42; N, 10.95. Found:
C, 54.35; H, 5.04; N, 10.96.
2-(4-Methylpiperazino)-4-(3-pyridyl)pyrimidine (11). This
compound was obtained as an oil in 84% yield. The hydrobro-
mide salt had mp 163–165ꢁC; 1H NMR (salt, deuterated di-
methyl sulfoxide): d 2.87(s, 3H), 3.13 (m, 2H), 3.37 (m, 2H),
3.55 (m, 2H), 4.91 (m, 2H), 7.55 (d, J ¼ 5 Hz, 1H), 7.91
(m, 1H), 8.66 (d, J ¼ 5 Hz, 1H), 8.92 (m, 2H), 9.53 (s, 1H),
9.93 ppm (br s, 2H).Anal. Calcd. for 22C14H17N5ꢃ4HBrꢃ3H2O:
C, 37.86; H, 4.99; N, 15.77. Found: C, 38.02; H, 4.66; N,
15.58.
4C14H20N4Oꢃ5HBrꢃ2H2O: C, 45.39; H, 6.05; N, 15.12. Found:
C, 45.71; H, 6.08; N, 15.27.
4-(3,4-Methylenedioxyphenyl)-2-(4-methylpiperazino)-pyrimi-
dine (18). This compound was obtained in 77% yielꢁd; mp
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(free base) 115–116 C; mp (hydrobromide salt) 287–288 C; H
NMR: d 2.39 (s, 3H), 2.57 (m, 4H), 3.96 (m, 4H), 6.06 (s,
2H), 6.88 (d, J ¼ 5 Hz, 1H), 6.92 (d, J ¼ 8 Hz, 1H), 7.61 (m,
2H), 8.36 ppm (d,
J
¼
5 Hz, 1H). Anal. Calcd. for
C16H18N4O2ꢃ2HBr: C, 41.76; H, 4.38; N, 12.18. Found: C,
41.58; H, 4.43; N, 12.12.
4-(1,4-Benzodioxane-4-yl)-2-(4-methylpiperazino)-pyrimidine
1
(19). This compound was obtained as an oil in 81% yield; H
NMR: d 2.38 (s, 3H), 2.57 (m, 4H), 3.96 (m, 4H), 4.33 (s,
4H), 6.89 (d, J ¼ 5 Hz, 1H), 6.97 (d, J ¼ 8 Hz, 1H), 7.57 (m,
1H), 7.68 (m, 1H), 8.35 ppm (d, J ¼ꢁ 5 Hz, 1H). The hydrobro-
mide salt had mp 297–298 C. Anal. Calcd. for
2C17H20N4O2ꢃ4HBrꢃH2O: C, 42.26; H, 4.80; N, 11.60. Found:
C, 42.29; H, 4.65; N, 11.55.
4-(2,3-Dimethoxy-1-naphthyl)-2-(4-methylpiperazino)-pyrimi-
dine (20). This compound was obtained as an oil in 70% yield;
1H NMR: d 2.37 (s, 3H), 2.51 (m, 4H), 3.85 (s, 3H), 3.93 (m,
4H), 4.05 (s, 3H), 6.69 (d, J ¼ 5 Hz, 1H), 7.27 (s, 1H), 7.32
(m, 1H), 7.42 (m, 1H), 7.59 (d, J ¼ 8 Hz, 1H), 7.78 (d, J ¼ 8
Hz, 1H), 8.47 ppm (d, J ¼ 5 Hz, 1H). The hydrobromide salt
had mp 240–241ꢁC. Anal. Calcd. for 4C21H23N4O2ꢃ4HBrꢃH2O:
C, 56.19; H, 5.50; N, 12.48. Found: C, 56.01; H, 5.68; N,
12.48.
4-(1-Methylindol-2-yl)-2-(4-methylpiperazino)pyrimidine (12).
This compound was obtained as an oil in 78%; 1H NMR: d
240 (s, 3H), 2.55 (m, 4H), 3.94 (m, 4H), 4.18 (s, 3H), 6.97 (d,
J ¼ 5 Hz, 1H), 7.06 (s, 3H), 7.19 (t, J ¼ 8 Hz, 1H), 7.36 (t, J
¼ 8 Hz, 1H), 7.45 (d, J ¼ 8 Hz, 1H), 7.70 (d, J ¼ 8 Hz, 1H),
8.38 ppm (d, J ¼ 5 Hz, 1H). The hydrobromide salt had mp
302–303ꢁC. Anal. Calcd. for 2C18H23N5ꢃ4HBrꢃH2O: C, 45.02;
H, 5.46; N, 14.58. Found: C, 45.10; H, 5.26; N, 14.47.
4-(2,20-Bithiophen-5-yl)-2-(4-methylpiperazino)-pyrimidine
1
(13). This compound was obtained as an oil in 76% yield; H
NMR: d 2.36 (s, 3H), 2.50 (m, 4H), 3.92 (m, 4H), 6.79 (d, J
¼ 5 Hz, 1H), 7.05 (t, J ¼ 4 Hz, 1H), 7.18 (d, J ¼ 4 Hz, 1H),
7.27 (m, 2H), 7.55 (d, J ¼ 4 Hz, 1H), 8.29 ppm (d, J ¼ 5 Hz,
1H). The hydrobromide salt had mp 187–190ꢁC. Anal. Calcd.
for 2C17H18N4S2ꢃ3HBrꢃ4H2O: C, 40.85; H, 4.74; N, 11.21.
Found: C, 40.54; H, 4.41; N, 11.04.
4-(1,3-Dithiane-2-yl)-2-(4-methylpiperazino)pyrimidine (14).
This compound was obtained as an oil in 69% yield; 1H
NMR: d 204 (m, 2H), 2.17 (m, 1H), 2.35 (s, 3H), 2.47 (m,
4H), 3.03 (m, 4H), 3.88 (m, 4H), 8.30 (d, J ¼ 5 Hz, 1H), 8.65
ppm (d, J ¼ 5 Hz, 1H). The hydrobromide salt had mp 175–
176ꢁC. Anal. Calcd. for C13H20N4S2ꢃ2HBr: C, 34.07; H, 4.84;
N, 12.23. Found: C, 34.30; H, 5.13; N, 12.02.
4-(1,3-Dioxolane-2-yl)-2-(4-methylpiperazino)pyrimidine (15).
This compound was obtained as an oil in 69% yield; 1H
NMR: d 233 (s, 3H), 2.46 (t, J ¼ 5 Hz, 4H), 3.87 (t, J ¼ 5
Hz, 4H), 4.10 (m, 4H), 5.60 (s, 1H), 6.66 (d, J ¼ 5 Hz, 1H),
8.34 ppm (d, J ¼ 5 Hz, 1H). The hydrobromide had mp 166–
170ꢁC. Anal. Calcd. for C12H18N4O2ꢃHBr: C, 43.53; H, 5.78;
N, 16.92. Found: C, 43.87; H, 5.87; N, 17.00.
4-(2-Methoxyphenyl)-2-(4-methylpiperazino)pyrimidine (21).
This compound was obtained in 88% yield; mp (free base)
ꢁ
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1
79–80 C; mp (hydrobromide salt) 191–192 C; H NMR: d 238
(s, 3H), 3.51 (m, 4H), 3.91 (s, 3H), 3.93 (m, 4H), 7.03 (d, J ¼
8Hz, 1H), 7.18 (t, J ¼ 8 Hz, 1H), 7.21 (d, J ¼ 5 Hz, 1H),
7.43 (m, 1H), 8.01 (d, J ¼ 8 Hz, 1H), 8.36 ppm (d, J ¼ 5 Hz,
1H). Anal. Calcd. for 2C16H20N4Oꢃ4HBrꢃH2O: C, 42.22; H,
5.09; N, 12.31. Found: C, 42.25; H, 5.06; N, 12.33.
4-(3-Methoxyphenyl)-2-(4-methylpiperazino)pyrimidine (22).
This compound was obtained as an oil in 80% yield; 1H
NMR: d 237 (s, 3H), 2.57 (m, 4H), 3.90 (s, 3H), 3.97 (m, 4H),
6.95 (d, J ¼ 5 Hz, 1H), 7.42 (t, J ¼ 8 Hz, 1H), 7.63 (m, 3H),
8.39 ppm (d, J ¼ 5 Hz, 1H). The hydrobromide had mp 244–
245ꢁC. Anal. Calcd. for 2C16H20N4Oꢃ4HBrꢃH2O: C, 42.20; H,
5.09; N, 12.31. Found: C, 42.18; H, 5.08; N, 12.35.
4-(4-Methoxyphenyl)-2-(4-methylpiperazino)pyrimidine (23).
This compound was obtained in 89% yield; mp (free base)
ꢁ
ꢁ
1
66–67 C; mp (hydrobromide salt) 278–279 C; H NMR: d 237
(s, 3H), 2.52 (m, 4H), 3.89 (s, 3H), 3.96 (m, 4H), 6.90 (d, J ¼
5 Hz, 1H), 6.98 (m, 2H), 8.04 (m, 2H), 8.34 ppm (d, J ¼ 5
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet