4662 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 23
Mickelson et al.
°C): IR (mineral oil) 1661, 1577, 1505, 1395, 1319, 1210, 1188
cm-1; 1H NMR (300 MHz, CDCl3) δ 8.16 (s, ArH), 7.4-7.5 (m,
ArH), 7.1-7.15 (m, ArH, 2 H), 5.40 (s, NCH2), 3.03 (dd, J )
8.4, 6.9 Hz, 2 H), 2.73 (dd, J ) 8.4, 6.9 Hz, 2 H), 2.2-2.35 (m,
CH), 1.2-1.4 (m, CH2CH2); MS (EI) m/ e 333, 292, 265, 69;
HRMS (EI) calcd for C18H15N5O2 (M+) 333.1226, found 333.1246.
Anal. (C18H15N5O2‚(H2O)1/2) C, H, N.
MgSO4), a semisolid was obtained which solidified overnight
to provide 1.55 g (67%) of the acylated intermediate as a white
solid (mp 139-142 °C). To a solution of the above intermediate
(1.20 g, 5.17 mmol) and triethylamine (1.00 mL, 7.17 mmol)
in acetonitrile (25 mL) was added mesyl azide21 (1.00 g, 8.26
mmol). The mixture was allowed to stir for 8 h at room
temperature followed by a basic workup (ethyl acetate, NaH-
CO3, H2O, brine, MgSO4). The resulting residue was triturated
with diethyl ether-hexane to provide 1.22 g (91%) of the diazo
compound as a yellow solid (mp 158-160 °C).
3-(5-Cyclop r op yl-1,2,4-oxa d ia zol-3-yl)-4,5-d ih yd r o-5-(1-
oxo-3-m eth yl-2-bu ten yl)im id a zo[1,5-a ]qu in oxa lin e (17a ).
A solution of 16 (0.53 g, 1.9 mmol), triethylamine (0.40 mL,
2.9 mmol), 4-(dimethylamino)pyridine (0.047 g), CH2Cl2 (20
mL), and DMF (4 mL) was cooled to 0 °C. A solution of 3,3-
dimethylacryloyl chloride (0.30 mL, 2.7 mmol) in CH2Cl2 (4
mL) was added dropwise, and the reaction mixture was
allowed to stir for 16 h at room temperature. After a basic
workup (CH2Cl2, NaHCO3, H2O, brine, MgSO4), the residue
was purified by flash chromatography (ethyl acetate) to provide
0.44 g (64%) of 17a as an off-white solid (mp 74-77 °C): IR
(mineral oil) 1659, 1576, 1507, 1498, 1365, 1165 cm-1; 1H NMR
(300 MHz, CDCl3) δ 8.13 (s, ArH), 7.20-7.60 (m, ArH, 4 H),
5.87 (s, 0.5 H, rotamer), 5.15-5.40 (m, 1.5 H, rotamer), 4.70-
4.95 (m, 0.5 H, rotamer), 3.15-3.30 (br s, 0.5 H, rotamer),
2.20-2.35 (m, CH), 2.12 (s, CCH3, 2 H, rotamer), 1.86 (s, CCH3,
2 H, rotamer), 1.60-1.90 (m, 2 H, rotamer), 1.20-1.40 (m,
CH2CH2); MS (EI) m/ e 361, 292, 279, 238, 210, 195, 102;
HRMS (EI) calcd for C20H19N5O2 (M+) 361.1539, found 361.1560.
Anal. (C20H19N5O2‚(H2O)1/5) C, H, N.
To a solution of the above diazo intermediate (1.25 g, 4.84
mmol) in THF (25 mL) was added 10% NaOH (5 mL). After
stirring for 1 h at room temperature, the mixture was
subjected to an aqueous workup (ethyl acetate, brine, MgSO4),
and the residue was triturated with diethyl ether to provide
0.720 g (69%) of 23 as a pale yellow powder (mp 185 °C dec):
1
IR (mineral oil) 2135, 1686, 1622, 1501 cm-1; H NMR (300
MHz, DMSO-d6) δ 10.74 (s, CONH), 7.45 (d, J ) 7.8 Hz, ArH),
7.20 (apparent t, J ) 6.9 Hz, ArH), 7.00-7.10 (m, ArH, 2 H),
5.92 (s, 1 H), 4.30 (s, NCH2); MS (EI) m/ e 216, 188, 160, 148,
131, 118; HRMS (EI) calcd for C10H8N4O2 (M+) 216.0647, found
216.0661.
1H-P yr r olo[1,2,3-d e]qu in oxa lin e-2,5(3H,6H)-d ion e (24).
To a solution of rhodium(II) trifluoroacetate dimer22 (40.0 mg,
0.061 mmol) in CH2Cl2 (50 mL) was added a slurry of 23 (390
mg, 1.80 mmol) in CH2Cl2 (50 mL) over 20 min at room
temperature. After an additional 10 min the solvent was
removed under reduced pressure, and the residue was tritu-
rated with diethyl ether-hexane to give a solid which was
further purified by flash chromatography (9:1 CH2Cl2:MeOH)
to provide 0.204 g (60%) of 24 as an off-white solid (mp 222-
9-(5-Cyclop r op yl-1,2,4-oxa d ia zol-3-yl)-4,5-d ih yd r o-4,4-
d im eth yl-6H,8H-im id a zo[1,5-a ]p yr id o[1,2,3-d e]qu in oxa -
lin -6-on e (18a ). A mixture of 17a (0.310 g, 0.858 mmol),
freshly sublimed aluminum trichloride (3.80 g, 28.5 mmol), and
1,2-dichlorobenzene (10 mL) was heated at 100 °C for 2.5 h.
The mixture was allowed to cool to room temperature, and the
reaction was quenched by the slow addition of H2O. After an
aqueous workup (CH2Cl2, H2O, brine, MgSO4), the residue was
purified by flash chromatography (19:1 CH2Cl2:MeOH) to
provide 0.195 g (63%) of 18a as a white powder (mp 199-202
226 °C): IR (mineral oil) 1718, 1713, 1684, 1647, 1502 cm-1
;
1H NMR (300 MHz, DMSO-d6) δ 10.68 (s, CONH), 6.8-6.9 (m,
ArH, 2 H), 6.65-6.75 (m ArH), 4.31 (s, 2 H), 3.59 (s, 2 H); MS
(EI) m/ e 188, 159, 131. Anal. (C10H8N2O2‚(H2O)1/4) C, H, N.
3-(5-Cyclop r op yl-1,2,4-oxa d ia zol-3-yl)-N -m e t h oxy-
im id a zo[1,5-a ]qu in oxa lin e-5(4H)-ca r boxa m id e (26).
A
1
°C): IR (mineral oil) 1672, 1574, 1364, 1319 cm-1; H NMR
solution of 16 (1.33 g, 4.76 mmol) and diisopropylethylamine
(0.95 mL, 5.5 mmol) in THF (40 mL) was cooled to 0 °C.
Triphosgene (0.510 g, 1.72 mmol) was added, and the solution
was allowed to stir for 3 h while warming to room temperature.
The solution was then cooled to 0 °C, diisopropylethylamine
(2.0 mL, 11 mmol) and methoxylamine hydrochloride (0.530
g, 6.35 mmol) were added, and the mixture was allowed to
warm to room temperature and stir for 16 h. After a basic
workup (ethyl acetate, NaHCO3, brine, MgSO4), the residue
was purified by flash chromatography (ethyl acetate) to provide
1.10 g (66%) of 26 as a white solid (mp 207-209 °C): IR
(mineral oil) 1672, 1571, 1500, 1482, 1279 cm-1; 1H NMR (300
MHz, CDCl3) δ 8.16 (s, 1 H), 8.02 (s, 1 H), 7.60-7.70 (m, ArH),
7.45-7.55 (m, ArH), 7.25-7.35 (m, ArH, 2 H), 5.20 (s, NCH2),
3.79 (s, OCH3), 2.15-2.30 (m, CH), 1.20-1.40 (m, CH2CH2);
MS (EI) m/ e 352, 278, 238, 210, 195; HRMS (EI) calcd for
C17H16N6O3 (M+) 352.1284, found 352.1306. Anal. (C17H16N6O3)
C, H, N.
(300 MHz, CDCl3) δ 8.13 (s, ArH), 7.47 (d, J ) 7.7 Hz, ArH),
7.15-7.30 (m, ArH, 2 H), 5.40 (s, NCH2), 2.58 (s, COCH2),
2.20-2.35 (m, CH), 1.36 (s, C(CH3)2, 6 H), 1.20-1.35 (m,
CH2CH2); MS (EI) m/ e 361, 292, 277, 263, 250, 235. Anal.
(C20H19N5O2‚(H2O)1/5) C, H, N.
1,2,3,4-Tetr a h yd r o-4-(1-oxo-3-p h en yl-(E)-2-p r op en yl)-
qu in oxa lin -2-on e (20). Cinnamoyl chloride (4.66 g, 28.0
mmol) was added in portions over 10 min to a mixture of 22
(3.15 g, 21.3 mmol), K2CO3 (5.00 g, 36.2 mmol), H2O (20 mL),
and acetone (10 mL) at 0 °C. The mixture was stirred at 0 °C
for 20 min and at room temperature for 3 h. The mixture was
poured into ice water. The solids were filtered, washed with
H2O and hot CH2Cl2, and dried to give 5.10 g (86%) of 20 as a
cream-colored solid (mp 271-273 °C): IR (mineral oil) 1690,
1
1659, 1503, 1361, 751 cm-1; H NMR (300 MHz, DMSO-d6) δ
10.82 (s, NH), 7.50-7.75 (m, 3 H), 7.15-7.45 (m, 5 H), 6.85-
7.15 (m, 3 H), 4.46 (s, NCH2CO); MS (EI) m/ e 278, 131, 103;
HRMS (EI) calcd for C17H14N2O2 (M+) 278.0155, found 278.1068.
1H,5H-P yr id o[1,2,3-d e]qu in oxa lin e-2,5(3H)-d ion e (21).
A mixture of 20 (2.22 g, 7.98 mmol), freshly sublimed alumi-
num trichloride (10.0 g, 75.0 mmol), and 1,2-dichlorobenzene
(20.0 mL) was heated at 120 °C for 4 h and allowed to cool to
room temperature. The mixture was poured into 100 mL of
ice-water and allowed to stand for 1 h. The resultant
precipitate was filtered, washed with copious amounts of water
and hexane, and dried in vacuo to give 1.56 g (98%) of 21 as
an off-white solid (mp >300 °C): IR (mineral oil) 1693, 1632,
1593, 1566, 1404 cm-1; 1H NMR (300 MHz, DMSO-d6) δ 11.04
(s, NH), 7.94 (d, J ) 9.6 Hz, CHdCH), 7.33 (d, J ) 6.6 Hz,
ArH), 7.16 (apparent t, J ) 7.7 Hz, ArH), 7.06 (d, J ) 7.3 Hz,
ArH), 6.65 (d, J ) 9.5 Hz, CHdCH), 4.52 (s, NCH2CO); MS
(EI) m/ e 200, 171. Anal. (C11H8N2O2‚(H2O)4/5) C, N; H: calcd,
4.51; found, 4.05.
8-(5-Cyclop r op yl-1,2,4-oxa d ia zol-3-yl)-4-m et h oxy-7H -
d iim id a zo[1,5-a :1′,5′,4′-d e]qu in oxa lin -5(4H)-on e (27).
A
solution of 26 (0.62 g, 1.76 mmol) in CH2Cl2 (15 mL) was cooled
to -40 °C. A solution of [bis(trifluoroacetoxy)iodo]benzene
(0.820 g, 1.91 mmol) in CH2Cl2 (5 mL) was added dropwise,
and the reaction mixture was allowed to stir for 3 h while
warming to 5 °C. After a basic workup (CH2Cl2, Na2CO3,
brine, MgSO4) the residue was purified by flash chromatog-
raphy (90:9:1 ethyl acetate:CH2Cl2:MeOH) to provide 0.16 g
(26%) of 27 as a white solid (mp 232-234 °C): IR (mineral
1
oil) 1718, 1521, 1508 cm-1; H NMR (300 MHz, DMSO-d6) δ
8.81 (s, ArH), 7.61 (d, J ) 7.7 Hz, ArH), 7.10-7.20 (m, 2 H,
ArH), 5.32 (s, NCH2), 4.03 (s, NOCH3), 2.35-2.50 (m, CH),
1.15-1.35 (m, CH2CH2); MS (EI) m/ e 350, 319, 281, 250, 236.
Anal. (C17H14N6O3‚(H2O)1/5) C, H, N.
2-Am in o-3-n itr oben zoic Acid (28). A solution of 2-chloro-
3-nitrobenzoic acid (5; 5.00 g, 24.8 mmol), ammonium hydrox-
ide (25.0 mL), and copper(I) chloride (50 mg) was heated in a
bomb at 125 °C for 20 h and allowed to cool to room
temperature. The solid residue was dissolved in water and
the solution acidified with 3 N HCl. The resultant orange
4-(2-Dia zoa cet yl)-1,2,3,4-t et r a h yd r oq u in oxa lin -2-on e
(23). A mixture of 22 (1.48 g, 9.99 mmol), diketene (1.00 mL,
13.0 mmol), 4-(dimethylamino)pyridine (0.020 g), and CH2Cl2
(20 mL) was heated at reflux for 2 h. After cooling to room
temperature and an aqueous workup (CH2Cl2, H2O, brine,