Methyl 7-Methyl-2-(methylthio)benzoxazole-4-carboxy-
late (10). A mixture of 6 (2.1 g, 9.5 mmol), anhydrous K2CO3 (5
g), and iodomethane (1.0 mL, 16 mmol) in acetone (200 mL) was
stirred rapidly at room temperature for 3 h. The reaction mixture
was filtered over Celite, the filter pad was washed with acetone
(50 mL), and the solvent was removed. The residue was
partitioned between EtOAc (75 mL) and H2O (20 mL), and the
organic phase was further washed with brine (20 mL), dried over
Na2SO4, and concentrated. The residue was purified by silica
gel column chromatography (25% EtOAc in hexanes, Rf 0.50)
and recrystallized from acetone/water to give 2.05 g (88%) of 10
as colorless needles: mp 102-103 °C; 1H NMR (400 MHz, CDCl3)
δ 2.53 (s, 3H), 2.83 (s, 3H), 3.99 (s, 3H), 7.08 (d, J ) 8.1 Hz,
1H), 7.85 (d, J ) 8.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
14.6, 15.4, 52.2, 118.0, 124.4, 125.5, 126.7, 141.2, 151.7, 165.7,
167.7. Anal. Calcd for C11H11NO3S: C, 55.68; H, 4.67; N, 5.90.
Found: C, 55.67; H, 4.61; N, 5.77.
Methyl 2-(3-Methoxy-6-methylpyridin-2-yl)-7-methyl-
benzoxazole-4-carboxylate (11). A 2.5 M solution of n-BuLi
in hexanes (0.75 mL, 1.88 mmol) was added dropwise over 5
min to 25 (370.4 mg, 1.83 mmol) dissolved in THF (5 mL) at
-78 °C. After a further 5 min, Me3SnCl (480.4 mg, 2.41 mmol)
dissolved in THF (2 mL) was added, the cooling bath was
removed, and the solution was allowed to attain room temper-
ature. CuBr (386.0 mg, 2.69 mmol) was added as a solid before
10 (283.6 mg, 1.20 mmol) and Pd(PPh3)4 (80.7 mg, 5 mol %)
dissolved in THF (5 mL) were added via syringe. The mixture
was then heated to reflux for 1.5 h. After cooling to room
temperature, Na4EDTA (1.2 g) and LiCl (1.1 g) in H2O (5 mL)
were added, and the mixture was refluxed in the air for 5.5 h.
The mixture was filtered through Celite, and the filter pad was
washed with THF (2 × 10 mL). The organic layer was washed
with new EDTA solution (1.2 g in 10 mL of H2O, pH ) 8) and
brine (2 × 10 mL), before being dried over Na2SO4 and
concentrated to dryness. Following silica gel column chroma-
tography (EtOAc, Rf 0.20) and recrystallization (EtOAc), 309.0
mg (83%) of 11 was obtained as colorless blocks: mp 140-142
°C; 1H NMR (400 MHz, CDCl3) δ 2.64 (s, 3H), 2.68 (s, 3H), 4.03
(s, 3H), 4.05 (s, 3H), 7.24 (d, J ) 7.9 Hz, 1H), 7.30 (d, J ) 8.6
Hz, 1H), 7.36 (d, J ) 8.6 Hz, 1H), 7.98 (d, J ) 7.9 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 15.8, 23.4, 52.3, 56.3, 120.0, 120.8,
126.1, 126.6, 126.9, 127.4, 133.9, 140.67, 150.2, 150.6, 154.4,
161.5. 166.1. Anal. Calcd for C17H16N2O4: C, 65.38; H, 5.16; N,
8.97. Found: C, 65.51; H, 5.17; N, 8.91.
In conclusion, palladium-catalyzed cross-coupling chem-
istry has been successfully applied in the model synthesis
of a precursor to pyridinyl boxazomycin C analogues. This
is also an example where thioether compounds provide
an attractive alternative when other coupling partners
cannot be used.
Experimental Section
3-Methoxy-6-methyl-2-(tributylstannyl)pyridine (4). A
2.5 M solution of n-BuLi in hexanes (1.76 mL, 4.40 mmol) was
added dropwise over 5 min to 25 (877.9 mg, 4.35 mmol) dissolved
in THF (11 mL) at -78 °C. After a further 5 min n-Bu3SnCl
(1.20 mL, 4.42 mmol) was added, the cooling bath was removed,
and the solution was allowed to attain room temperature.
Saturated aqueous NH4Cl (2 mL) was added, and the mixture
was stirred vigorously. Ether (30 mL) was added, and the organic
solution was washed with water (10 mL) and brine (10 mL),
dried over Na2SO4, and concentrated. The residue was purified
by chromatography on alumina (hexanes/EtOAc, 100:1) to give
1
4 as a colorless oil, 1.70 g (98%). H NMR (400 MHz, CDCl3) δ
0.88 (t, J ) 7.3 Hz, 9H), 1.10 (m, 6H), 1.33 (m, 6H), 1.55 (m,
6H), 2.49 (s, 3H), 3.74 (s, 3H), 6.86 (d, J ) 8.5 Hz, 1H), 6.91 (d,
J ) 8.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 9.5, 13.2, 23.1,
26.8, 28.6, 54.7, 113.9, 120.8, 150.6, 158.2, 162.7. Anal. Calcd
for C19H35NOSn: C, 55.37; H, 8.56; N, 3.40. Found: C, 55.48;
H, 8.65; N, 3.12.
Methyl 7-Methyl-2-oxo-2,3-dihydrobenzoxazole-4-car-
boxylate (6). A mixture of 57 (2.5 g, 15 mmol) and CDI (4.1 g,
25 mmol) in THF (50 mL) was refluxed with stirring for 2 h.
The reaction mixture was filtered over Celite while hot, the filter
pad was washed with THF (2 × 25 mL), and the solvent was
removed. The residue was partitioned between CHCl3 (150 mL)
and 2 N HCl (75 mL), and the organic layer was further washed
with 2 N HCl (75 mL), water (75 mL), and brine (25 mL), dried
over Na2SO4, and concentrated. The residue was crystallized
from EtOAc to give 2.0 g (69%) of 6 as colorless needles: mp
220-221 °C; 1H NMR (400 MHz, CDCl3) δ 2.43 (s, 3H), 3.97 (s,
3H), 6.96 (d, J ) 8.1 Hz, 1H), 7.62 (d, J ) 8.1 Hz, 1H); 9.2 (br s,
1H); 13C NMR (100 MHz, CDCl3) δ 14.9, 52.4, 110.3, 123.6, 124.3,
125.7, 130.9, 142.6, 154.2, 165.6. Anal. Calcd for C10H9NO4: C,
57.97; H, 4.38; N, 6.76. Found: C, 57.90; H, 4.30; N, 6.67.
Methyl 7-Methyl-2-thioxo-2,3-dihydro-benzoxazole-4-
carboxylate (8). CS2 (2.0 g, 26 mmol) was added dropwise with
stirring to KOH (2.6 g, 46 mmol) dissolved in an ethanol/water
mixture (2.5:1, 35 mL) to give a clear yellow solution. The
hydrochloride salt of 57 (5.0 g, 23 mmol) was added as a solid,
and the mixture was brought to reflux with stirring for 2 h. The
contents were poured into hot water (100 mL), and AcOH (2 mL)
was added to precipitate the product. The yellow solid was
collected by filtration and recrystallized from ethanol/water to
Acknowledgment. This work was financially sup-
ported by Pfizer Global Research and Development. We
thank Dr. Maruta Boyd for NMR assistance.
1
Supporting Information Available: 1H and 13C NMR
spectra for compounds 4, 6, 8, 10, and 11. LC-MS spectra for
compounds 4, 6, 8, 10, 11. This material is available free of
give 3.4 g (66%) of 8 as colorless needles: mp 100-102 °C; H
NMR (400 MHz, CDCl3) δ 2.50 (s, 3H), 3.98 (s, 3H), 7.08 (d, J )
8.2 Hz, 1H), 7.71 (d, J ) 8.2 Hz, 1H); 10.40 (br s, 1H); 13C NMR
(100 MHz, CDCl3) δ 15.0, 52.6, 110.4, 125.1, 125.6, 126.2, 131.4,
147.8, 165.1, 180.8. Anal. Calcd for C10H9NO3S: C, 53.80; H,
4.06; N, 6.27. Found: C, 53.67; H, 4.10; N, 6.20.
JO0510033
7438 J. Org. Chem., Vol. 70, No. 18, 2005