1080
M. Colombo, M. Giglio and I. Peretto
Vol 45
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yield. M.p. 115-116°C. H NMR (300 MHz, CDCl3): ꢁ 8.53 (s,
2H), 7.41-7.51 (m, 4H), 7.35 (m, 1H), 5.03 (bs, 1H), 4.13-4.26
(m, 1H), 1.29 (d, J = 6.5 Hz, 6H). ESI+MS: calcd for C13H15N3:
213.13; found: 214.1 (MH+). Elem. Anal.: calcd: C, 73.2%; H,
7.1%; N, 19.7%. Found: C, 73.4%; H, 7.2%; N, 19.8%.
work-up and purification procedures based on silica
cartridge.
The synthetic method was applied to the
functionalization of dihalo-pyrimidine structures, but
good unpublished results were also obtained with bromo-
and iododerivatives of aryl derivatives and indole
derivatives.
Isopropyl-(5-p-tolyl-pyrimidin-2-yl)-amine (23). Prepared
according to procedure 2 (reaction time: 6h) described for the
compound 20 in 94% yield. M.p. 124-125°C. H NMR (300
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MHz, CDCl3): ꢁ 8.51 (s, 2H), 7.38 (m, 2H), 7.25 (m, 2H), 5.02
(bs, 1H), 4.20 (m, 1H), 2.41 (s, 3H), 1.29 (d, J = 6.5 Hz, 6H).
ESI+MS: calcd for C14H17N3: 227.14; found: 228.1 (MH+). Elem.
Anal.: calcd: C, 74.0%; H, 7.5%; N, 18.5%. Found: C, 73.9%;
H, 7.3%; N, 18.4%.
EXPERIMENTAL
All the MW-assisted reactions were performed in sealed tube
with an Emrys Optimizer – Biotage MW oven. 1H spectra were
recorded in CDCl3 or DMSO-d6 solution as indicated, using a
Bruker Avance II – 300 MHz instrument. The MS-spectra were
recorder using a micromass ZQ Waters spectrometer, ionization
method: positive ESI. Abbreviations: DME: 1,2-dimethoxy-
ethane, TBAB: tetrabutyl ammonium bromide, Pd(dppf)Cl2:
1,1'-bis(diphenylphosphino)ferrocene dichloro palladium(II).
General procedure A: Suzuki coupling. A mixture of 1 (0.3
mmol), arylboronic acid (0.36 mmol), KF (0.6 mmol) and
Pd(OAc)2 (5% mol) in MeOH (1.5 mL) was heated in a sealed
tube at 120°C for 20 min by MW irradiation. The solvent was
evaporated and the crude was purified by silica cartridge
(petroleum ether/EtOAc).
General procedure B: Suzuki coupling. To a solution of 1
(0.3 mmol) and Pd(PPh3)4 (5% mol) in DME (3 mL),
arylboronic acid (0.36 mmol) and Na2CO3 (2 M aqueous
solution, 0.6 mmol) were added. The mixture was refluxed for
16h and then the solvent was evaporated. The solvent was
evaporated and the crude was purified by flash chromatography
(petroleum ether/EtOAc).
Phenyl-(5-phenyl-pyrimidin-2-yl)-amine (24). Prepared
according to procedure 2 (reaction time: 6h, temperature: 130°C)
described for the compound 20 in 78% yield. M.p. 168-169°C.
1H NMR (300 MHz, DMSO-d6): ꢁ 9.74 (s, 1H), 8.83 (s, 2H),
7.77-7.83 (m, 2H), 7.68-7.75 (m, 2H), 7.44-7.52 (m, 2H), 7.37
(m, 1H), 7.25-7.34 (m, 2H), 6.93-7.02 (m, 1H). ESI+MS: calcd
for C16H13N3: 247.11; found: 248.2 (MH+). Elem. Anal.: calcd:
C, 77.7%; H, 5.3%; N, 17.0%. Found: C, 77.9%; H, 5.4%; N,
17.2%.
2-Methoxy-5-p-tolyl-pyrimidine (25). To a solution of
sodium methylate (prepared dissolving 9 mg (0.39 mmol) of
sodium in 1.5 mL of MeOH at room temperature), 2-chloro-5-
tolyl-pyrimidine (61 mg, 0.3 mmol) was added and the mixture
was heated by MW oven (100°C, 10min). The solvent was
evaporated, the residue suspended in water (5 mL) and extracted
with EtOAc (2ꢀ5 mL). The organic layers were dried over
Na2SO4 and the solvent was evaporated under reduced pressure.
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Yield: 98%. M.p. 80-81°C (lit. [9], 82-83°C) H NMR (300
MHz, DMSO-d6): ꢁ 8.90 (s, 2H), 7.61 (m, 2H), 7.31 (m, 2H),
3.96 (s, 3H), 2.36 (s, 3H). ESI+MS: calcd for C12H12N2O:
200.09; found: 201.1 (MH+). Elem. Anal.: calcd: C, 72.0%; H,
6.0%; N, 14.0%. Found: C, 71.9%; H, 6.2%; N, 14.2%.
Yields, 1H-NMR and ESI+MS data of compounds 2-19,
prepared according to general procedure A or B, are reported in
Table 2.
2-Isopropoxy-5-p-tolyl-pyrimidine (26). Prepared according
to the procedure described for the compound 25 in 96% yield.
M.p. 79-80°C. 1H NMR (300 MHz, CDCl3): ꢁ 8.69 (s, 2H), 7.42
(m, 2H), 7.29 (m, 2H), 5.34 (m, 1H), 2.42 (s, 3H), 1.44 (d, J =
6.2 Hz, 6H). ESI+MS: calcd for C14H16N2O: 228.13; found:
229.2 (MH+). Elem. Anal.: calcd: C, 73.7%; H, 7.1%; N, 12.3%.
Found: C, 73.9%; H, 7.2%; N, 12.2%.
4-(5-Phenyl-pyrimidin-2-yl)-morpholine (20).
Procedure 1. A mixture of 2 (57 mg, 0.3 mmol) and
morpholine (0.8 mL, 9 mmol) was stirred at room temperature
for 16 h. 1 N HCl was added until pH 2-3 and then the mixture
was extracted with CH2Cl2 (2ꢀ30 mL). The collected organic
layers were dried over Na2SO4 and the solvent was evaporated
under reduced pressure. Yield: 95%.
Procedure 2. A mixture of 2 (57 mg, 0.3 mmol) and
morpholine (52 μL, 0.6 mmol) in THF (1.5 mL) was heated by
MW oven (100°C, 10min). The solvent was evaporated and the
crude was purified by silica cartridge (petroleum ether/EtOAc
9:1). Yield: 93%.
M.p. 142-143°C. 1H NMR (300 MHz, CDCl3): ꢁ 8.58 (s, 2H),
7.42-7.52 (m, 4H), 7.36 (m, 1H), 3.85-3.89 (m, 4H), 3.78-3.84
(m, 4H). ESI+MS: calcd for C14H15N3O: 241.12; found: 242.1
(MH+). Elem. Anal.: calcd: C, 69.7%; H, 6.3%; N, 17.4%.
Found: C, 69.8%; H, 6.2%; N, 17.6%.
2-Ethylsulfanyl-5-p-tolyl-pyrimidine (27). To a solution of
sodium ethanethiolate (prepared dissolving 9 mg (0.39 mmol) of
sodium and 111 μL (1.5 mmol) of ethanethiol in 1.5 mL of dry
THF at room temperature), 2-chloro-5-p-tolyl-pyrimidine (61
mg, 0.3 mmol) was added and the mixture was heated by MW
oven (100°C, 20min). The solvent was evaporated, the residue
suspended in water (5 mL) and extracted with EtOAc (2ꢀ5 mL).
The organic layers were dried over Na2SO4 and the solvent was
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evaporated under reduced pressure. Yield: 93%. H NMR (300
MHz, CDCl3): ꢁ 8.73 (s, 2H), 7.44 (m, 2H), 7.31 (m, 2H), 3.22
(q, J = 7.3 Hz, 2H), 2.42 (s, 3H), 1.45 (t, J = 7.3 Hz, 3H).
ESI+MS: calcd for C13H14N2S: 230.09; found: 231.1 (MH+).
Elem. Anal.: calcd: C, 67.8%; H, 6.1%; N, 12.2%. Found: C,
68.0%; H, 6.2%; N, 12.3%.
4-(5-p-Tolyl-pyrimidin-2-yl)-morpholine (21). Prepared
according to procedures 1 and 2 described for the compound 20
in 87% and 81% yield, respectively. M.p. 157-158°C. H NMR
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(300 MHz, CDCl3): ꢁ 8.57 (s, 2H), 7.39 (m, 2H), 7.27 (m, 2H),
3.79-3.89 (m, 8H), 2.41 (s, 3H). ESI+MS: calcd for C15H17N3O:
255.14; found: 256.1 (MH+). Elem. Anal.: calcd: C, 70.6%; H,
6.7%; N, 16.5%. Found: C, 70.5%; H, 6.7%; N, 16.4%.
Isopropyl-(5-phenyl-pyrimidin-2-yl)-amine (22). Prepared
according to procedure 1 described for the compound 20 in 92%
2-Chloro-4-phenyl-pyrimidine (28). A mixture of 2,4-
dichloro-pyrimidine (68 mg, 0.45 mmol), phenylboronic acid
(66 mg, 0.54 mmol), KF (52 mg, 0.9 mmol) and Pd(OAc)2 (5%
mol) in MeOH (2.2 mL) was heated in a sealed tube at 120°C
for 20 min by MW irradiation. The solvent was evaporated and
the crude was purified by short chromatographic column