Notes
J . Org. Chem., Vol. 64, No. 3, 1999 1013
TLC on silica gel, 2.1:1 hexane/EtOAc, Rf ) 0.30. Pure material
was obtained by crystallization from hexane, mp 65-65.4 °C,
light yellow plates: molecular ion calcd for C10H9NO 159.06840,
found m/e ) 159.0679, error ) 3 ppm; base peak ) 159 amu; IR
(KBr, cm-1) 3124, dC-H; 1106, C-O; 300 MHz NMR (CDCl3,
ppm) δ 7.88 (1H, s), 7.54 (2H, d, J ) 8.1 Hz), 7.29 (1H, s), 7.23
(2H, d, J ) 8.1 Hz), 2.38 (3H, s); 13C NMR (75.4 MHz, CDCl3,
ppm) 151.7, 150.1, 138.6, 129.6, 125.0, 124.3, 120.8, 21.3.
5-Ca r beth oxyoxa zole (5c). The method of Scho¨llkopf et al.
was used with modifications.7 To a solution of methyl isocyanide
(8.0 mL, 146 mmol) in 150 mL of THF at -78 °C was added
n-BuLi (154 mmol, 1.54 M in hexanes) dropwise over 20 min.
The pale yellow suspension was stirred for 1 h and then
transferred via a thick cannula (cooled with dry ice wrapped in
aluminum foil) to a vigorously stirred solution of diethyl oxalate
(22 mL, 162 mmol) in 50 mL of THF at -78 °C over 5 min. The
cooling bath was removed, the yellow solution was allowed to
warm to room temperature over 2 h, and 12 mL of AcOH was
added. After concentration (aspirator), 100 mL of aqueous
NaHCO3 was added to the residue, and the mixture was
extracted with 3 × 100 mL of ether and dried (Na2SO4). After
removal of solvent (aspirator) the residue was purified by flash
chromatography on silica gel (4.5 × 20 cm), 500 mL of 3:1
hexane/ether followed by 500 mL of 2:1 hexane/ether, followed
by 400 mL of 1:1 hexane/ether eluent, 20 mL fractions. Fractions
37-70 contained 14.6 g (71%) of 5c as colorless liquid. Analytical
TLC on silica gel, 2.1:1 hexane/EtOAc, Rf ) 0.35. 5c: molecular
ion calcd for C6H7NO3 141.04260, found m/e ) 141.0423, error
) 2 ppm; base peak ) 113 amu; IR (neat, cm-1) 3132, dC-H;
1734, CdO; 300 MHz NMR (CDCl3, ppm) 8.03 (1H, s), 7.78 (1H,
s), 4.41 (2H, q, J ) 7.1 Hz), 1.40 (3H, t, J ) 7.1 Hz);. 13C NMR
(75.4 MHz, CDCl3, ppm) 157.5, 153.2, 142.7, 133.2, 61.6, 14.2.
5-(2-P h en yleth yl)oxa zole (5d ). The method of Scho¨llkopf
et al. was used with modifications.7 To a solution of methyl
isocyanide (1.1 mL, 20 mmol) in 20 mL of THF at -78 °C was
added n-BuLi (21 mmol, 1.60 M in hexanes) dropwise over 5
min. The pale yellow suspension was stirred for 10 min. A
solution of ethyl hydrocinnamate (3.22 g, 18.1 mmol) in 15 mL
of THF was added dropwise via cannula over 5 min. The cooling
bath was removed, and the tan solution was allowed to warm
to room temperature over 3 h. The reaction was quenched with
50 mL of brine, extracted with ether (2 × 50 mL), and dried
(Na2SO4). After removal of solvent (aspirator), the residue was
purified by flash chromatography on silica gel (2.5 × 20 cm),
1:1 hexane/ether eluent, 15 mL flash fractions. Fractions 7-12
contained 2.36 g (75%) of 5d as a colorless liquid. Analytical TLC
on silica gel, 2.1:1 hexane/EtOAc, Rf ) 0.35. 5d : molecular ion
calcd for C11H11NO 173.08410, found m/e ) 173.0842, error ) 1
ppm; IR (neat, cm-1) 3128, dC-H; 1510, CdC; 300 MHz NMR
(CDCl3, ppm) 7.74 (1H, s) 7.30-7.14 (5H, m) 6.71 (1H, s) 2.94
(4H, s); 13C NMR (75.4 MHz, CDCl3, ppm) 151.9, 149.9, 140.2,
128.3, 128.1, 126.1, 122.1, 33.6, 27.1.
5-(ter t-Bu tyld im eth ylsilyloxyp r op yl)oxa zole (5e). The
method of J acobi et al. was used.8a To a solution of methyl
isocyanide (1.0 mL, 19 mmol) in 130 mL of THF at -78 °C was
added n-BuLi (21 mmol, 1.54 M in hexanes) dropwise, and the
solution was stirred for 40 min. A solution of γ-butyrolactone
(1.3 mL, 16.9 mmol) in 10 mL of THF was added dropwise via
cannula. The cooling bath was removed, and the tan solution
was allowed to warm to room temperature over 3 h. DMF (30
mL) was added to the suspension. After ca. 16 h, glacial acetic
acid (1.6 mL) was added, and the mixture was allowed to stir
for an additional hour. The mixture was concentrated (aspirator),
combined with concd NaHCO3 (80 mL), and extracted with CH2-
Cl2 (6 × 30 mL). The combined organic layers were washed with
brine, dried (MgSO4), and concentrated, and the crude alcohol
was dissolved in 30 mL of CH2Cl2. A solution of DMAP (58 mg,
0.46 mmol) in 10 mL of CH2Cl2 was added, followed by i-Pr2-
NEt (4.42 mL, 25.4 mmol). The solution was cooled to 0 °C, and
TBSCl (3.26 g, 20.3 mmol) in 10 mL of CH2Cl2 was added. After
30 min, the ice bath was removed and the reaction mixture was
warmed to room temperature for 2.5 h. The mixture was poured
onto H2O (30 mL), extracted with CH2Cl2 (3 × 10 mL), and dried
(MgSO4). After removal of solvent (aspirator) the residue was
purified by flash chromatography on silica gel, 8:1 hexane/EtOAc
eluent, fraction volume of 15 mL after an initial fraction of 60
mL; fractions 12-27 contained 2.54 g (62%) of 5e as yellow
liquid. Analytical TLC on silica gel, 4:1 hexane/EtOAc, Rf ) 0.37.
5e: molecular ion calcd for C12H24NO2Si 242.1576, found m/e )
242.1570 (M + 1), error ) 2 ppm; base peak ) 184 amu; IR (neat,
cm-1) 3124, dC-H; 2929, C-H; 300 MHz NMR (CDCl3, ppm)
7.76 (1H, s), 6.77 (1H, t, J ) 1.2 Hz), 3.65 (2H, t, J ) 6.2 Hz),
2.75 (2H, dt, J ) 1.2, 7.5 Hz), 1.90-1.81 (2H, m), 0.90 (9H, s),
0.05 (6H, s); 13C NMR (75.4 MHz, CDCl3, ppm) 152.8, 149.9,
121.9, 61.7, 30.5, 25.8, 21.7, 18.2, -5.4.
Gen er a l P r oced u r e for th e Syn th esis of 4-Iod ooxa zole
Der iva tives 8a -c. Meth od A. To a solution of hexamethyldi-
silazane (HMDS, 0.16 mL, 0.758 mmol, Aldrich, distilled from
CaH2) in 0.50 mL of THF cooled to 0 °C was added n-BuLi (0.50
mL, 1.49 M in hexane, Aldrich). The solution was stirred for 10
min at 0 °C and then warmed to room temperature for an
additional 20 min. In a separate flask, the oxazole substrate
5a -c (ca. 0.627 mmol) was dissolved in a mixture of 1.6 mL of
THF/1.25 mL of DMPU, cooled to -78 °C, and the LiHMDS
solution was added via cannula. After 1 h, a solution of I2 (182
mg, 0.716 mmol, Mallinckrodt) in 2.1 mL of THF was added
dropwise by syringe over a 15 min period. The mixture was
stirred for 1 h at -78 °C and then poured onto a mixture of ether
(50 mL) and 10% Na2S2O3 (10 mL). The organic layer was
washed with H2O (2 × 25 mL), dried (MgSO4), and purified as
described for specific examples.
4-Iod o-5-(p-tolyl)oxa zole (8a ). Reactants (general method
A): 5-(p-tolyl)oxazole (5a ) (100 mg, 0.627 mmol), I2 (182 mg,
0.716 mmol, Mallinckrodt), and 0.75 mmol of LiHMDS. After
removal of solvent (aspirator), the residue was purified by flash
chromatography on EM silica gel 60 (20 × 2 cm), 4:1 hexane/
ether eluent; 15 mL fractions with an initial fraction of 30 mL.
Fractions 2-4 contained 13 mg (5%) of 2,4-diiodooxazole 10a ;
fractions 5-10 contained 131 mg (73%) of a mixture of 8a :9a ,
97:3 by 1H NMR analysis; fractions 17-23 contained 14 mg of
recovered oxazole 5a . 8a : TLC on silica gel, 2.1:1 hexane/EtOAc,
Rf ) 0.46. Pure material was obtained by crystallization from
hexane: mp 40.0-41 °C, light yellow rods; molecular ion calcd
for C10H8INO 284.96530, found m/e ) 284.9656, error ) 1 ppm;
base peak ) 285 amu; IR (KBr, cm-1) 3093, dC-H; 1491, CdC;
300 MHz NMR (CDCl3, ppm) 7.87 (1H, s), 7.85 (2H, d, J ) 8.1
Hz), 7.27 (2H, d, J ) 8.1 Hz), 2.40 (3H, s); 13C NMR (75.4 MHz,
CD2Cl2, ppm) 151.5, 150.9, 139.9, 129.7, 126.3, 124.5, 77.3, 21.5.
2-Iodo-5-(p-tolyl)oxazole (9a ): TLC on silica gel, 2.1:1 hexane/
EtOAc, Rf ) 0.46. Pure material was obtained by crystallization
from hexane: mp 112-112.5 °C, light yellow needles; molecular
ion calcd for C10H8INO 284.96530; found m/e ) 284.9647, error
) 2 ppm; base peak ) 285 amu; IR (KBr, cm-1) 3024, dC-H;
1506, CdC; 300 MHz NMR (CDCl3, ppm) 7.50 (2H, d, J ) 8.3
Hz), 7.25-7.22 (3H, m), 2.39 (3H, s); 13C NMR (75.4 MHz, CD2-
Cl2, ppm) 158.0, 139.6, 129.9, 124.7, 124.5, 124.4, 99.8, 21.5. 2,4-
Diiodo-5-(p-tolyl)oxazole (10a ): TLC on silica gel, 2.1:1 hexane/
EtOAc, Rf ) 0.59. Pure material was obtained by crystallization
from ether/hexane: mp 147-148 °C, light yellow rods; molecular
ion calcd for C10H7I2NO 410.86220, found m/e ) 410.8606, error
) 4 ppm; base peak ) 411 amu; IR (KBr, cm-1) 3024, dC-H;
1456, CdC; 1170, C-O; 300 MHz NMR (CDCl3, ppm) 7.79 (2H,
d, J ) 8.1 Hz), 7.27 (2H, d, J ) 8.1 Hz), 2.41 (3H, s); 13C NMR
(125.7 MHz, CD2Cl2, ppm) δ 157.7, 140.5, 129.7, 126.3, 123.7,
100.7, 78.8, 21.5.
4-Iod o-5-p h en yloxa zole (8b). Reactants (general method
A): 5-phenyloxazole (5b) (90 mg, 0.623 mmol), I2 (181 mg, 0.714
mmol, Mallinckrodt), and 0.75 mmol of LiHMDS. After removal
of solvent (aspirator), the residue was purified by flash chro-
matography on EM silica gel 60 (20 × 2 cm), 4:1 hexane/ether
eluent; 15 mL fractions with an initial fraction of 30 mL.
Fractions 1-3 contained 3 mg (1%) of 2,4-diiodooxazole 10b ;
fractions 4-10 contained 114 mg (67%) of 8b:9b, 97:3 ratio by
1H NMR analysis; fractions 13-20 contained 4 mg of recovered
oxazole 5b. 8b: TLC on silica gel, 2.1:1 hexane/EtOAc, Rf ) 0.47.
Pure material was obtained by crystallization from ether/
hexane: mp 103-104 °C, light yellow hexagonal rods; molecular
ion calcd for C9H6INO 270.94960, found m/e ) 270.9489, error
) 3 ppm; base peak ) 271 amu; IR (KBr, cm-1) 3124, dC-H;
1495, CdC; 300 MHz NMR (CDCl3, ppm) 7.96 (2H, d, J ) 7.7
Hz), 7.89 (1H, s), 7.48-7.35 (3H, m); 13C NMR (75.4 MHz, CDCl3,
ppm) δ 151.3, 150.4, 129.2, 128.6, 126.9, 126.1, 77.6. 2,4-Diiodo-
5-phenyloxazole (10b): TLC on silica gel, 2.1:1 hexane/EtOAc,
Rf ) 0.54. Pure material was obtained by crystallization from