PHOSPHORUS, SULFUR, AND SILICON
3
400 MHz, 13C NMR with 100 MHz). IR spectra were recorded ν 3297, 1641, 1587, 1505, 710 cm−1. Anal. Calcd for C18H18N4S:
on a Shimadzu IR-440 infrared spectrophotometer using KBr C, 67.05; H, 5.63; N, 17.38; found: C, 67.20; H, 5.86; N, 17.14.
discs. The elemental analysis was measured by an Elementary
Vario EL III analyzer. The Supplemental Materials contains sam-
N-(4-Isopropylphenyl)-6-methyl-2-((pyridin-3-ylmethyl)thio)
ple 1H and 13C NMR spectra of products 4 (Figures S 1 - S 16).
pyrimidin-4-amine (4c). Yield 71%, pale yellow solid, m.p.
All reagents were acquired from commercial sources and
used without further purification.
1
105.5–106.1°C. H NMR (400 MHz, CDCl3): δ 8.66 (d, J =
1.6 Hz, 1H, Py-H), 8.46 (dd, J = 1.6, 4.8 Hz, 1H, Py-H), 7.73
(dd, J = 2.0, 8.0 Hz, 1H, Py-H), 7.18–7.26 (m, 5H, Ph-H +
Py-H), 7.03 (brs, 1H, NH), 6.21 (s, 1H, Pyrim-H), 4.33 (s, 2H,
CH2), 2.85–2.95 (m, 1H, CH-(CH3)2), 2.27 (s, 3H, Pyrim-CH3),
1.24 (d, J = 6.8 Hz, 6H, CH-(CH3)2); 13C NMR (100 MHz,
CDCl3): δ 169.3, 166.0, 161.1, 150.0, 147.8, 145.4, 136.5, 135.6,
134.6, 127.1, 123.3, 122.7, 98.9, 33.5, 31.8, 23.9, 23.8; IR (KBr): ν
3266, 1640, 1580, 1513, 709 cm−1. Anal. Calcd for C20H22N4S:
C, 68.54; H, 6.33; N, 15.99; found: C, 68.22; H, 6.55; N, 15.73.
Chemistry
Synthesis of -chloro--methyl--((pyridin--ylmethyl)thio)
pyrimidine ()
A mixture of intermediate 2 (2.34 g, 10 mmol) and POCl3
(15 mL) was stirred at 90°C for 3 h. After completion of the
reaction, most of the POCl3 was removed under reduced pres-
sure. The residue was poured into ice water, extracted with
dichloromethane, dried over anhydrous MgSO4, and evaporated
under vacuum. The obtained oil was purified by chromatogra-
phy on silica gel with petroleum ether/acetone (3:1 v/v) to give
compound 3 as pale yellow oil, yield 90%. 1H NMR (400 MHz,
CDCl3): δ 8.71 (d, J = 1.6 Hz, 1H, Py-H), 8.48 (dd, J = 1.6,
4.8 Hz, 1H, Py-H), 7.78 (dd, J = 2.0, 8.0 Hz, 1H, Py-H), 7.22–
7.25 (m, 1H, Py-H), 6.88 (s, 1H, Pyrim-H), 4.35 (s, 2H, CH2),
2.44 (s, 3H, CH3); IR (KBr): ν 1634, 1556, 1517, 716 cm−1. Anal.
Calcd for C11H10N3SCl: C, 52.22; H, 4.03; N, 16.55; found: C,
52.48; H, 4.00; N, 16.69.
N-(4-Methoxyphenyl)-6-methyl-2-((pyridin-3-ylmethyl)thio)
pyrimidin-4-amine (4d). Yield 61%, pale yellow solid, m.p.
97.5–98.1°C. 1H NMR (400 MHz, CDCl3): δ 8.66 (d, J = 1.6 Hz,
1H, Py-H), 8.46 (dd, J = 1.6, 4.8 Hz, 1H, Py-H), 7.74 (dt, J = 2.0,
7.6 Hz, 1H, Py-H), 6.90–7.23 (m, 5H, Ph-H + Py-H), 6.70 (brs,
1H, NH), 6.06 (s, 1H, Pyrim-H), 4.33 (s, 2H, CH2), 3.82 (s, 3H,
OCH3), 2.26 (s, 3H, Pyrim-CH3); 13C NMR (100 MHz, CDCl3):
δ 169.4, 166.2, 161.8, 157.3, 150.2, 148.0, 136.5, 134.6, 130.5,
125.5, 123.3, 114.5, 98.3, 55.5, 31.9, 23.9; IR (KBr): ν 3297, 1641,
1577, 1501, 710 cm−1. Anal. Calcd for C18H18N4OS: C, 63.88;
H, 5.36; N, 16.56; found: C, 63.65; H, 5.51; N, 16.23.
General procedure for synthesis of N-(substituted phenyl)-
-methyl--((pyridin--ylmethyl)thio) pyrimidin--amine ()
The appropriate substituted aniline (9.6 mmol) was added to
a mixture of intermediate 3 (2.02 g, 8 mmol) and the equiva-
lent of DIPEA in dioxane (20 mL). The reaction mixture was
refluxed for 4 h, and then concentrated under reduced pressure.
The residue was purified by chromatography on silica gel with
petroleum ether/acetone (5:1 v/v) to give compound 4.
N-(4-Fluorophenyl)-6-methyl-2-((pyridin-3-ylmethyl)thio)
pyrimidin-4-amine (4e). Yield 55%, pale yellow solid, m.p.
174.6–176.3°C. 1H NMR(400 MHz, DMSO-d6): δ 9.47 (brs, 1H,
NH), 8.58 (d, J = 2.0 Hz, 1H, Py-H), 8.40 (dd, J = 1.6, 4.8 Hz,
1H, Py-H), 7.75 (dt, J = 2.0, 8.0 Hz, 1H, Py-H), 7.03–7.55 (m,
5H, Ph-H + Py-H), 6.28 (s, 1H, Pyrim-H), 4.33 (s, 2H, CH2),
2.27 (s, 3H, Pyrim-CH3); 13C NMR (100 MHz, DMSO-d6):
δ 168.5, 164.8, 160.2, 159.0, 156.6, 149.8, 147.9, 136.2, 135.6,
134.5, 123.3, 122.3, 122.2, 115.4, 115.2, 100.9, 31.0, 23.3; IR
(KBr): ν 3293, 1640, 1587, 1505, 710 cm−1. Anal. Calcd for
C17H15N4SF: C, 62.56; H, 4.63; N, 17.17; found: C, 62.84; H,
4.50; N, 16.97.
N-Phenyl-6-methyl-2-((pyridin-3-ylmethyl)thio)pyrimidin-4-
amine (4a). Yield 81%, pale yellow solid, m.p. 136.4–137.3°C.
1H NMR (400 MHz, CDCl3): δ 8.66 (d, J = 2.0 Hz,1H, Py-H),
8.46 (dd, J = 1.6, 4.8 Hz, 1H, Py-H), 7.75 (dt, J = 2.0, 8.0 Hz,
1H, Py-H), 7.16–7.39 (m, 6H, Ph-H + Py-H), 6.73 (brs, 1H,
NH), 6.25 (s, 1H, Pyrim-H), 4.35 (s, 2H, CH2), 2.30 (s, 3H,
Pyrim-CH3); 13C NMR (100 MHz, CDCl3): δ 169.6, 166.5,
160.9, 150.2, 148.1, 138.0, 136.5, 134.5, 129.3, 124.8, 123.3,
122.5, 99.0, 32.0, 23.9; IR (KBr): ν 3294, 1641, 1581, 1501,
716 cm−1. Anal. Calcd for C17H16N4S: C, 66.21; H, 5.23; N,
18.17; found: C, 66.55; H, 5.61; N, 18.05.
N-(3-Chlorophenyl)-6-methyl-2-((pyridin-3-ylmethyl)thio)
pyrimidin-4-amine (4f). Yield 51%, pale yellow solid, m.p.
1
158.7–160.0°C. H NMR (400 MHz,CDCl3): δ 8.66 (d, J =
1.6 Hz, 1H, Py-H), 8.46 (dd, J = 1.6, 4.8 Hz, 1H, Py-H), 7.74
(m, 1H, Py-H), 7.09–7.47 (m, 5H, Ph-H + Py-H), 6.91 (brs,
1H, NH), 6.22 (s, 1H, Pyrim-H), 4.36 (s, 2H, CH2), 2.32 (s,
3H, Pyrim-CH3); 13C NMR (100 MHz, CDCl3 + DMSO-d6):
δ 168.5, 164.9, 159.8, 149.6, 147.8, 140.9, 136.1, 134.2, 133.0,
129.9, 123.1, 121.7, 119.2, 117.9, 101.6, 31.0, 23.3; IR (KBr): ν
3290, 1644, 1576, 1499, 716 cm−1. Anal. Calcd for C17H15N4SCl:
C, 59.56; H, 4.41; N, 16.34; found: C, 59.48; H, 4.67; N 16.28.
N-(4-Methylphenyl)-6-methyl-2-((pyridin-3-ylmethyl)thio)
pyrimidin-4-amine (4b). Yield 89%, pale yellow solid, m.p.
1
133.9–135.0°C. H NMR (400 MHz, CDCl3): δ 8.65 (d, J =
2.0 Hz, 1H, Py-H), 8.46 (dd, J = 0.8, 4.8 Hz, 1H, Py-H), 7.73 (d,
J = 8.0 Hz, 1H, Py-H), 7.16–7.22 (m, 5H, Ph-H + Py-H), 7.02
(brs, 1H, NH), 6.17 (s, 1H, Pyrim-H), 4.33 (s, 2H, CH2), 2.34 (s,
3H, Ph-CH3), 2.26 (s, 3H, Pyrim-CH3); 13C NMR (100 MHz, N-(4-Chlorophenyl)-6-methyl-2-((pyridin-3-ylmethyl)thio)
CDCl3): δ 169.5, 166.3, 161.2, 150.2, 148.0, 136.5, 135.2, pyrimidin-4-amine (4g). Yield 53%, pale yellow solid, m.p.
1
134.8, 134.6, 129.9, 123.3, 123.0, 98.7, 32.0, 23.9, 20.9; IR (KBr): 186.1–187.1°C. H NMR (400 MHz, CDCl3): δ 8.66 (d, J =