Synthesis of Dimethyl Sulfomycinamate
J . Org. Chem., Vol. 61, No. 14, 1996 4631
the tube was opened and the solvent evaporated. The residue
was then purified by flash column chromatography on silica
gel to give the cross-coupled product.
to dryness. Purification by flash column chromatography on
silica gel (CH2Cl2:MeOH ) 95:5) gave 17.8 mg (86%) 37 as a
white solid: mp 122.0-123.5 °C; 1H NMR (CDCl3) δ 2.75 (3H,
s), 7.28 (1H, ddd, J ) 1.2, 4.8, 7.6 Hz), 7.81 (1H, dt, J ) 1.8,
7.6 Hz), 8.00 (1H, m), 8.42 (1H, s), 8.62 (1H, m); IR (CH2Cl2)
ν 1706 cm-1; HRMS calcd for C10H8N2O2 188.0586, found
188.0586.
Meth yl 6-Am in o-2-p yr id in eca r boxyla te (40). A mixture
of N-(6-methyl-2-pyridyl)acetamide42 (39, 20.0 g, 0.13 mol) and
water (200 mL) was heated at 75 °C until a homogeneous
solution was formed. Then KMnO4 (50.0 g, 0.31 mol) was
added in small portions over 40 min with vigorous magnetic
stirring. The purple reaction mixture was kept at 75 °C for a
further 3 h. The reaction mixture was then filtered through
Celite while still hot. The filtrate was concentrated to about
50 mL. Concentrated HCl was then added to adjust the pH
of the solution to 4-5 (pH paper), whereupon a large amount
of white solid formed. The white solid was collected by
filtration and dried under vacuum to afford 16.5 g of crude
material. This crude product was mixed with a methanol
solution saturated with HCl (200 mL) and refluxed overnight.
The solvent was removed in vacuo and the residue partitioned
2-(4-Meth oxyp h en yl)-4-p h en yloxa zole (19). Prepared in
91% yield by a coupling reaction between 13 and 15 using the
general procedure described above. Purification of 19 by flash
column chromatography on silica gel (petroleum ether:CH2-
1
Cl2 ) 1:1) afforded 19 as a white solid: mp 97.5-99.0 °C; H
NMR (CDCl3) δ 3.87 (3H, s), 6.99 (2H, d, J ) 8.8 Hz), 7.33
(1H, t, J ) 7.5 Hz), 7.43 (2H, t, J ) 7.5 Hz), 7.81 (2H, d, J )
7.5 Hz), 7.92 (1H, s), 8.05 (2H, d, J ) 8.8 Hz). Anal. Calcd
for C16H13NO2: C, 76.47; H, 5.22; N, 5.58, found C, 76.38; H,
5.31; N, 5.32.
2-(4-Meth oxyp h en yl)-4-(2-p yr id yl)oxa zole (20). (1) Pre-
pared in 85% yield by a coupling reaction between 13 and 16
using the general procedure described above. Purification of
20 by flash column chromatography on silica gel (petroleum
ether:ethyl acetate ) 2:1) afforded 20 as a white solid: mp
1
131.0-132.0 °C; H NMR (CDCl3) δ 3.88 (3H, s), 7.00 (2H, d,
J ) 9.0 Hz), 7.22 (1H, dd, J ) 7.5, 7.8 Hz), 7.78 (1H, t, J ) 7.8
Hz), 8.01 (1H, d, J ) 7.8 Hz), 8.07 (2H, d, J ) 9.0 Hz), 8.27
(1H, s), 8.60 (1H, d, J ) 7.5 Hz); 13C NMR (CDCl3) δ 55.3,
114.2, 120.2, 120.3, 122.6, 128.2, 136.1, 136.7, 142.0, 149.4,
between water and CH2
Cl2. Solid sodium bicarbonate was
151.0, 161.5, 162.1; IR (KBr) ν 2910 cm-1
. Anal. Calcd for
added to the two-layer mixture until gas evolution (CAUTION)
ceased. The organic layer was then separated, dried over
sodium sulfate, and evaporated to dryness. The residue was
purified by flash column chromatography on silica gel (CH2-
Cl2:ethyl acetate ) 1:1) to give 10.27 g (52%) of 40 as a white
solid: mp 84.6-85.5 °C; 1H NMR (CDCl3) δ 3.96 (3H, s), 4.72
(2H, br, s), 6.68 (1H, d, J ) 8.0 Hz), 7.48-7.60 (2H, m); 13C
NMR (CDCl3) δ 33.3, 113.3, 116.4, 138.9, 146.9, 159.0, 166.6;
C15H12N2O2: C, 71.42; H, 4.79; N, 11.10, found C, 71.36; H,
4.96; N, 10.96.
(2) Into a sealable tube were introduced bromo ketone 35
(100 mg, 0.50 mmol), amide 10 (150 mg, 1.0 mmol), and
anhydrous toluene (10 mL). The tube was sealed and heated
at 100 °C for 3 days. After evaporation of the solvent, the
residue was purified by flash column chromatography on silica
gel (petroleum ether:ethyl acetate ) 7:3) to give 85 mg (68%),
20, which was identical with the product from the coupling
reaction of 13 and 16.
IR (CH2Cl2) ν 3382, 1724 cm-1
. Anal. Calcd for C7H8N2O2:
C, 55.26; H, 5.30; N, 18.41, found C, 54.91; H, 5.51; N, 18.18.
Meth yl 6-Am in o-5-br om o-2-p yr id in eca r boxyla te (41)
an d Meth yl 6-Am in o-3-br om o-2-pyr idin ecar boxylate (42).
To a solution of 40 (11.8 g, 77.6 mmol) in CHCl3 (500 mL) was
added a solution of bromine (4.00 mL, 77.6 mmol) in CHCl3
(100 mL) over 1 h. The reaction mixture was stirred at room
temperature for 40 h. Then the reaction mixture was washed
with saturated aqueous sodium thiosulfate solution (100 mL)
and water (100 mL). The solvent was removed in vacuo, and
the residue was purified by flash column chromatography on
silica gel (petroleum ether:ethyl acetate ) 2:1) to give 4.48 g
(25%) of 41, 4.48 g (25%) of 42, and 2.95 g (25%) of recovered
2-(4-Meth oxyp h en yl)-4-vin yloxa zole (21). Prepared in
94% yield by a coupling reaction between 13 and 17 using the
general procedure described above. Purification of 21 by flash
column chromatography on silica gel (petroleum ether:ethyl
acetate ) 7:3) afforded 21 as a pale yellow oil: 1H NMR
(CDCl3) δ 3.85 (3H, s), 5.35 (1H, dd, J ) 1.5, 10.5 Hz), 6.00
(1H, dd, J ) 1.5, 16.8 Hz), 6.55 (1H, dd, J ) 10.5, 16.8 Hz),
6.96 (2H, d, J ) 9.0 Hz), 7.56 (1H, s), 8.00 (2H, d, J ) 9.0 Hz).
2-(4-Met h oxyp h en yl)-4-(p h en ylet h yn yl)oxa zole (22).
Prepared in 92% yield by a coupling reaction between 13 and
18 using the general procedure described above. Purification
of 22 by flash column chromatography on silica gel (petroleum
ether:ethyl acetate ) 2:1) afforded 22 as a white solid: mp
1
40. 41: white solid; mp 144.2-145.0 °C; H NMR (CDCl3) δ
3.96 (3H, s), 5.29 (2H, br, s), 7.36 (1H, d, J ) 7.9 Hz), 7.78
(1H, d, J ) 7.9 Hz); 13C NMR (CDCl3) δ 53.4, 109.7, 117.0,
141.5, 145.8, 156.1, 166.0; IR (CH2Cl2) ν 3275, 1742 cm-1. Anal.
Calcd for C7H7BrN2O2: C, 36.39; H, 3.05; N, 12.12, found C,
36.42; H, 2.99; N, 12.01. 42: white solid; mp 94.1-95.2 °C;
1H NMR (CDCl3) δ 3.97 (3H, s), 4.68 (2H, br, s), 6.50 (1H, d, J
) 8.7 Hz), 7.64 (1H, d, J ) 8.7 Hz); IR (CH2Cl2) ν 3466, 1730
1
113.8-115.0 °C; H NMR (CDCl3) δ 3.86 (3H, s), 6.98 (2H, d,
J ) 8.9 Hz), 7.36 (3H, m), 7.56 (2H, m), 7.87 (1H, s), 8.02 (2H,
d, J ) 8.9 Hz); 13C NMR (CDCl3) δ 55.4, 79.3, 92.6, 114.2, 119.5,
122.4, 124.8, 128.3, 128.7, 131.6, 140.5, 161.7, 161.8. Anal.
Calcd for C18H13NO2: C, 78.53; H, 4.76; N, 5.09, found C, 78.26;
H, 4.89; N, 4.69.
cm-1
. Anal. Calcd for C7H7BrN2O2: C, 36.39; H, 3.05; N,
12.12, found C, 36.57; H, 2.95; N, 11.92.
2-(1-Meth yleth en yl)-4-(2-p yr id yl)oxa zole (36). Bromo
ketone 3540 (211 mg, 1.05 mmol) and methacrylamide (28) (178
mg, 2.1 mmol) were dissolved in THF (20 mL, freshly distilled)
in a sealable tube. The tube was sealed and the mixture
heated at 100 °C for 3 days. After being cooled to room
temperature, the tube was opened and solvent evaporated. The
resulting solid was purified by flash column chromatography
on silica gel (petroleum ether:ethyl acetate ) 7:3) to give 120
Meth yl 6-(N-Acetyla m in o)-5-br om o-2-p yr id in eca r box-
yla te (43). A solution of 41 (5 mg) in Ac2O (0.5 mL) was
heated at 60-70 °C for 1.5 h. Then the solvent was removed
in vacuo, which resulted in a white solid (∼5 mg). A small
sample of 43 was purified by recrystallization from CH2Cl2/
hexane as a white solid: mp 167.5-169.0 °C; 1H NMR (CDCl3)
δ 2.53 (3H, s), 3.98 (3H, s), 7.75 (1H, d, J ) 8.1 Hz), 7.92 (1H,
br, s), 8.02 (1H, d, J ) 8.1 Hz); 13C NMR (CDCl3) δ 25.4, 53.7,
122.5, 143.4, 145.9, 149.2, 165.4, 171.4; IR (CH2Cl2) ν 3240,
1
mg (62%) of 36 as a white solid: mp 60.2-60.8 °C; H NMR
(CDCl3) δ 2.24 (3H, d), 5.43 (1H, d, J ) 1.3 Hz), 6.02 (1H, d, J
) 1.3 Hz), 7.20 (1H, dt, J ) 1.3, 8.7 Hz), 7.77 (1H, dt, J ) 1.0,
8.7 Hz), 7.93 (1H, d, J ) 5.9 Hz), 8.20 (1H, s), 8.59 (1H, dd, J
1724, 1682 cm-1
.
Meth yl 6-(N-Acetyla m in o)-3-br om o-2-p yr id in eca r box-
yla te (44). A solution of 42 (5 mg) in Ac2O (0.5 mL) was
heated at 60-70 °C for 1.5 h. Then the solvent was removed
in vacuo, which gave 44 as a white solid (∼5 mg): mp 140-
141 °C; 1H NMR (CDCl3) δ 2.19 (3H, s), 3.98 (3H, s), 7.94 (1H,
d, J ) 8.8 Hz), 8.06 (1H, br, s), 8.23 (1H, d, J ) 8.8 Hz); 13C
NMR (CDCl3) δ 25.3, 53.8, 113.4, 117.8, 144.8, 147.3, 150.3,
) 1.0, 5.9 Hz); IR (KBr) ν 3121 cm-1
. Anal. Calcd for
C11H10N2O: C, 70.95; H, 5.41; N, 15.04, found C, 70.68; H, 5.33;
N, 14.91.
2-Acetyl-4-(2-p yr id yl)oxa zole (37). To a solution of 36
(20 mg, 0.11 mmol) in 10 mL of 1:1 dioxane/water under a
nitrogen atmosphere were added one drop (ca. 0.03 mL) of
an OsO4 solution in CH3CN (500 mg of OsO4 in 25 mL of CH3-
CN) and sodium periodate (44 mg, 0.20 mmol). The mixture
was stirred at room temperature for 1 h. The solution was
extracted with CH2Cl2, washed with aqueous Na2S2O5 solution,
water, and brine, and then dried over Na2SO4 and evaporated
165.6, 169.4; IR (CH2Cl2) ν 3222, 1742, 1665 cm-1
.
3-Br om o-6-ca r bom eth oxy-2(1H)-p yr id in on e (45). To a
solution of 41 (0.942 g, 4.3 mmol) in 9 N sulfuric acid (100
mL) at 0 °C was added a solution of sodium nitrite (0.940 g,
13.6 mmol) in water (10 mL) dropwise over 10 min. The