(s, 3H), 2.97 (t, J ) 6.4 Hz, 2H), 2.54 (t, J ) 6.4 Hz, 2H), 2.21 (s,
3H), 1.87-1.82 (m, 2H), 1.71-1.68 (m, 2H); MS (pos. APCI):
m/z 355.1.
(CDCl3, 360 MHz): 7.98 (m, 1H), 7.33-7.29 (m, 1H), 7.16-7.14
(m, 1H), 6.97-6.92 (m, 2H), 6.87-6.80 (m, 1H), 6.11 (s, 1H),
3.63 (s, 3H), 2.53 (s, 3H); MS (pos. APCI): m/z 394.
2-(3-Methoxyphenyl)-4-(4-methoxyphenyl)-5,6,7,8-tetrahyd-
roquinoline-3-carbonitrile (4d). Purification by flash chromatog-
raphy on silica gel (ethyl acetate/CH2Cl2/hexanes 1:3:10) provided
product 4d (yield 93%) as a light yellow solid, mp 143-145 °C;
1H NMR (CDCl3, 360 MHz): 7.46-7.37 (m, 3H), 7.26-7.23 (m,
2H), 7.04-7.00 (m, 3H) 3.87 (s, 6H), 3.09 (t, J ) 6.4 Hz, 2H),
2.54 (t, J ) 6.4 Hz, 2H), 1.96-1.89 (m, 2H), 1.78-1.74 (m, 2H);
MS (pos. APCI): m/z 371.3.
Methyl 4-(2-Chloro-4-fluorophenyl)-6-methyl-2-thien-2-yl-
1,4-dihydropyrimidine-5-carboxylate (6f). 1H NMR (CDCl3, 360
MHz): 7.47-7.46 (m, 1H), 7.40-7.39 (m, 1H), 7.32-7.27 (m,
1H), 7.15-7.12 (m, 1H), 7.06-7.04 (m, 1H), 6.95-6.92 (m, 1H),
6.01 (s, 1H), 3.63 (s, 3H), 2.57 (s, 3H); MS (pos. APCI): m/z 365,
(neg.APCL) m/z 363.
Procedure for the Bis-Carbon-Carbon Cross-Coupling of
S-Ethyl 6-Methyl-4-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimi-
dine-5-carbothioate (7) with Phenylboronic Acid. A dry micro-
wave process vial was charged with DHPM 732 (43.9 mg, 0.15
mmol), phenylboronic acid (73.2 mg, 0.6 mmol), CuTC (143 mg,
0.75 mmol), Pd(OAc)2 (5.05 mg, 0.023 mmol, 15 mol %), and PPh3
(11.8 mg, 0.045 mmol, 30 mol %). The reaction vessel was sealed
and flushed with Ar. Through the septum of the microwave vessel
was added anhydrous and degassed dioxane (1 mL). The mixture
was subsequently heated in a microwave reactor at 130 °C for 1 h.
After cooling to ambient temperature, the solvent was evaporated
and the crude mixture diluted with ethyl acetate (50 mL) and
extracted with 10% aqueous ammonia (3 × 15 mL). The organic
layer was dried over MgSO4 and then concentrated under reduced
pressure. The residue was purified by column chromatography on
silica gel (CHCl3/hexanes 5:1) to provide 29.1 mg (55%) of
5-benzoyl-6-methyl-2,4-diphenyl-1,4-dihydropyrimidine 8 as a yel-
2-(4-Chlorophenyl)-4-(4-methoxyphenyl)-5,6,7,8-tetrahydro-
quinoline-3-carbonitrile (4e). Purification by flash chromatography
on silica gel (ethyl acetate/CH2Cl2/hexanes 1:3:13) provided product
1
4e (yield 77%) as a offwhite solid, mp 197-199 °C; H NMR
(DMSO-d6, 360 MHz): 7.84 (d, J ) 8.6 Hz, 2H), 7.60 (d, J ) 8.6
Hz, 2H), 7.36 (d, J ) 8.8 Hz, 2H), 7.09 (d, J ) 8.8 Hz, 2H), 3.83
(s, 3H), 2.99 (t, J ) 6.4 Hz, 2H), 2.54-2.47 (m, 2H), 1.86-1.81
(m, 2H), 1.70-1.65 (m, 2H); MS (pos. APCI): m/z 375.2.
2-(4-Cyanophenyl)-4-(4-methoxyphenyl)-5,6,7,8-tetrahydro-
quinoline-3-carbonitrile (4f). Purification by flash chromatography
on silica gel (ethyl acetate/CH2Cl2/hexanes 1:4:13) provided product
4f (yield 76%) as a yellow solid, mp 198-201 °C; 1H NMR
(DMSO-d6, 360 MHz): 8.04-7.99 (m, 4H), 7.38 (d, J ) 8.6 Hz,
2H), 7.10 (d, J ) 8.6 Hz, 2H), 3.83 (s, 3H), 3.01 (t, J ) 6.3 Hz,
2H), 2.53-2.50 (m, 2H), 1.87-1.84 (m, 2H), 1.72-1.68 (m, 2H);
13C NMR (DMSO-d6, 90 MHz): 161.9, 160.2, 156.2, 154.1, 142.5,
132.8, 131.2, 130.4, 130.3, 127.7, 118.6, 117.5, 114.6, 112.6, 106.1,
55.7, 33.5, 27.3, 22.3, 22.2; MS (pos. APCI): m/z 366.3.
General Procedure for Carbon-Carbon Cross-Coupling of
Dihydropyrimidine (5) with Arylboronic Acids (Table 4). A dry
microwave process vial was charged with the corresponding
dihydropyrimidine (DHPM) 5 (0.25 mmol), the corresponding
arylboronic acid (0.38 mmol), CuTC (143 mg, 0.75 mmol), and
Pd(PPh3)4 (3-8 mol %). The reaction vessel was flushed with Ar
and sealed. Through the septum anhydrous and degassed THF (5
mL) was added. The mixture was subsequently heated in a
microwave reactor at 100 °C for 25-60 min. After cooling, the
mixture was transferred to a round-bottom flask and adsorbed on
silica gel. The residue was purified by flash chromatography on
silica gel (ethyl acetate/hexanes 1:3) to provide desired DHPMs 6
as semisolids. The analytical and spectroscopic data were in
agreement with those previously reported.18
1
low oil, H NMR (DMSO-d6, 360 MHz): 7.91 (d, J ) 7.3, 2H),
7.56-7.44 (m, 8H), 7.32-7.20 (m, 5H), 5.70 (s, 1H), 1.84 (s, 3H);
MS (pos. APCI): m/z 353.4.
5-Bromo-2-phenylpyridine (10) (Scheme 3). Following the
general procedure for the carbon-carbon cross-coupling of thioa-
mides with phenylboronic acid (see above) and purification by flash
chromatography on silica gel (THF/hexanes 1:10), product 10 was
obtained in 87% yield as a light yellow solid, mp 72-75 °C, lit.51
1
mp 74-76 °C. H NMR (DMSO-d6, 360 MHz): 8.78 (d, J ) 2.3
Hz, 1H), 8.12 (dd, J1 ) 8.5 Hz, J2 ) 2.3 Hz, 1H), 8.08-8.06 (m,
2H), 7.95 (d, J ) 8.5 Hz, 1H), 7.52-7.43 (m, 3H);52 MS (pos.
APCI): m/z 233.9.
2,5-Diphenylpyridine 11 (Scheme 3). A microwave process vial
was charged with a stir bar. To the vessel were added 5-bromo-
2-phenylpyridine 10 (15 mg, 0.06 mmol), PhB(OH)2 (11.7 mg, 0.10
mmol), Pd(PPh3)4 (7.4 mg, 0.006 mmol, 10 mol %), and 1,2-
dimethoxyethane (0.75 mL). To the reaction mixture was added a
solution of Na2CO3 (10.2 mg, 0.10 mmol) in H2O (0.25 mL). The
reaction vessel was sealed and irradiated at 150 °C for 30 min.
After cooling, the mixture was transferred to a round-bottom flask,
and adsorbed on silica gel. The residue was purified by flash
chromatography on silica gel (ethyl acetate/CH2Cl2/hexanes 1:3:
20) to provide 12.5 mg (90%) of 2,5-diphenylpyridine 11 as a white
Ethyl 6-Methyl-2,4-diphenyl-1,4-dihydropyrimidine-5-car-
boxylate (6a). 1H NMR (CDCl3, 360 MHz): 7.67 (d, J ) 7.5 Hz,
2H) 7.45-7.37 (m, 5H), 7.31-7.23 (m, 3H), 5.74 (s, 1H), 4.11 (q,
J ) 7.1 Hz, 2H), 2.45 (s, 3H), 1.21 (t, J ) 7.1 Hz, 3H);50 13C
NMR (CDCl3, 90 MHz): 145.0, 133.6, 131.2, 128.8, 128.5, 127.5,
127.1, 126.7, 59.9, 57.3, 29.7, 14.2.
Methyl 4-(2-Chloro-4-fluorophenyl)-6-methyl-2-phenyl-1,4-
dihydropyrimidine-5-carboxylate (6b). 1H NMR (CDCl3, 360
MHz): 7.65 (d, J ) 7.2 Hz, 2H), 7.46-7.37 (m, 3H), 7.32-7.28
(m, 1H), 7.16-7.13 (m, 1H), 6.94-6.89 (m, 1H), 6.08 (s, 1H),
3.62 (s, 3H), 2.55 (s, 3H); MS (pos. APCI): m/z 359, (neg.
APCI): m/z 357.
Methyl 4-(2-Chloro-4-fluorophenyl)-2-(4-chlorophenyl)-6-
methyl-1,4-dihydropyrimidine-5-carboxylate (6c). 1H NMR
(CDCl3, 360 MHz): 7.62 (d, J ) 7.1 Hz, 2H), 7.37 (d, J ) 7.1 Hz,
2H), 7.32-7.27 (m, 1H), 7.18-7.15 (m, 1H), 6.97-6.92 (m, 1H),
6.08 (s, 1H), 3.64 (s, 3H), 2.56 (s, 3H); MS (pos. APCI): m/z 393.
Methyl 4-(2-Chloro-4-fluorophenyl)-6-methyl-2-(3-methylphe-
nyl)-1,4-dihydropyrimidine-5-carboxylate (6d). 1H NMR (CDCl3,
360 MHz): 7.51 (m, 1H), 7.41-7.39 (m, 1H), 7.32-7.28 (m, 3H),
7.16-7.13 (m, 1H), 6.95-6.90 (m, 1H), 6.07 (s, 1H), 3.62 (s, 3H),
2.56 (s, 3H), 2.36 (s, 3H); MS (pos. APCI): m/z 373.
1
solid, mp 170-172 °C, lit.53 mp 174-175 °C. H NMR (DMSO-
d6, 360 MHz): 8.99 (d, J ) 2.4 Hz, 1H), 8.17 (dd, J1 ) 8.3 Hz, J2
) 2.4 Hz, 1H), 8.16-8.13 (m, 2H), 8.05 (d, J ) 8.3 Hz, 1H), 7.79
(d, J ) 7.4 Hz, 2H), 7.54-7.41 (m, 6H);54 MS (pos. APCI): m/z
232.4.
General Procedure for Carbon-Sulfur Cross-Coupling of
Thioamides (3, 9, 5a) with Phenylboronic Acid (Scheme 4). A
microwave process vial was charged with 0.16 mmol of the
corresponding thioamide, PhB(OH)2 (77 mg, 0.63 mmol), Cu(OAc)2
(28.7 mg, 0.16 mmol), 1,10-phenanthroline (56.9 mg, 0.32 mmol),
and 1,2-dichlorethane (1.5 mL). The reaction mixture was stirred
under air for 15 min. After that time the reaction vessel was sealed
and irradiated at 110 °C for 30-120 min. After cooling, the mixture
(51) Tilley, J. W.; Zawoiski, S. J. Org. Chem. 1988, 53, 386.
(52) Comins, D. L.; Mantlo, N. B. J. Heterocycl. Chem. 1983, 20, 1239.
(53) Wiley, R. H.; Callahan, P. X.; Jarboe, C. H.; Nielsen, J. T.;
Wakefield, B. J. J. Org. Chem. 1960, 25, 366.
Methyl 4-(2-Chloro-4-fluorophenyl)-2-(2,6-difluorophenyl)-
6-methyl-1,4-dihydropyrimidine-5-carboxylate (6e). 1H NMR
(54) Kagabu, S.; Ando, C.; Ando, J. J. Chem. Soc., Perkin Trans. 1 1994,
739.
(50) Weis, A. L. Synthesis 1985, 528.
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