4368 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 19
Pirrung et al.
dd, J ) 10.5, 18.6 Hz), 3.87 (1H, dd, J ) 4.8, 18.3 Hz), 3.80
(3H, s), 3.04 (3H, s). 13C NMR: δ 161.09, 156.54, 128.75,
119.59, 114.24, 91.16, 55.36, 36.28, 35.71. FAB MS (M + H):
256. Anal. (C11H13NO4S) C, H, N.
3 (0.335, 1.99 mmol) was added to a solution of vinyl phos-
phinate 19 (0.335 g, 1.99 mmol) in 25 mL of CH2Cl2. Et3N (0.28
mL, 2 mmol) was added to the solution, and it was stirred at
room temperature for 1 d. The solution was evaporated onto
silica gel and purified by flash chromatography (2.5% EtOH
in CH2Cl2, Rf ) 0.1) to give 0.37 g of 20. This was dissolved in
15 mL of CH2Cl2 and treated with 0.6× mL (4.7 mmol) of
bromotrimethylsilane. The solution was stirred for 3 d at room
temperature. Water was added (1 mL), and the solution was
stirred for 3 h. The solution was evaporated, and the crude
residue was recrystallized from a few milliliters of EtOH to
give 0.21 g (41%) of 21; mp 182-183 °C. IR (Nujol): 1609,
3-(4-Meth oxyp h en yl)-4,5-d ih yd r o-isoxa zole-5-ca r box-
ylic Acid Hyd r oxym eth yl-a m id e (15). Chloro-oxime 23
(0.38 mmol, 70 mg) was stirred in 5 mL of THF. N-Hydroxy-
methyl acrylamide (48% solution in water, 74 µL, 0.38 mmol)
was added followed by Et3N (0.38 mmol, 53 µL). A white
precipitate immediately formed. After 20 min, the filtrate was
evaporated, MeOH (5 mL) was added, and the mixture was
sonicated. The resultant solid was filtered giving 25 mg (26%)
of nearly pure product. An analytical sample could be obtained
by chromatography (3:1 EtOAc:Hex, Rf ) 0.2); mp 152 °C (dec).
IR (Nujol): 3353, 3300, 1663, 1611, 1518, 1462, 1254, 1050
1
1516, 1464, 1306, 1253, 1179, 985 cm-1. H NMR (DMSO-d6):
δ 7.61 (2H, d, J ) 8.4 Hz), 6.99 (2H, d, J ) 8.7 Hz), 4.68 (1H,
ddd, J ) 4.8, 9.9, 15 Hz), 3.78 (3H, s), 3.75-3.39 (2H, m), 1.35
(3H, d, J ) 14.4 Hz). 31P NMR: δ 41.29. 13C NMR: δ 160.55,
155.56 (d, J ) 7.5 Hz), 128.25, 120.92, 114.11, 77.19 (d, J )
109 Hz), 55.27, 36.05, 12.18 (d, J ) 93 Hz). FAB MS (M + H):
256. Anal. (C11H14NO4P) C, H, N.
1
cm-1. H NMR (acetone-d6): δ 8.08 (1H, bs), 7.66 (2H, d, J )
9 Hz), 6.99 (2H, d, J ) 9 Hz), 5.05 (1H, dd, J ) 6.3, 11.7 Hz),
4.78-4.70 (2H, m), 3.84 (3H, s), 3.68 (1H, dd, J ) 11.4, 16.8
Hz), 3.59 (1H, dd, J ) 6.3, 16.8 Hz). 13C NMR: δ 169.95,
160.61, 155.69, 128.25, 120.83, 114.14, 78.55, 62.29, 55.27,
37.95. FAB MS (M + H): 251. HRMS m/z calcd for C12H14N2O4,
250.0954; found, 250.0943.
Th iop r op ion ic Acid S-[3-(4-Meth oxyp h en yl)-4,5-d ih y-
d r o-isoxa zol-5-ylm eth yl)ester (22). Chloro-oxime 3 (2.74
mmol) was generated in situ as described in the synthesis of
6. CH2Cl2 (10 mL) was added followed by allyl thiopropionate
(2.7 mmol, 0.37 mL). After it was stirred overnight, the
solution was evaporated onto silica gel and purified by flash
chromatography (3:1 Hex:EtOAc, Rf ) 0.52) to give 0.487 g
(64%) of a white solid; mp 62 °C. IR (thin film): 2990, 2979,
[3-(4-Meth oxyp h en yl)-4,5-d ih yd r o-isoxa zol-5-yl]p h os-
p h on ic Acid Dieth yl Ester (16). Chloro-oxime 3 (2.74 mmol)
was generated in situ as described in the synthesis of 6.
Diethyl vinylphosphonate (2.74 mmol, 0.42 mL) was added
followed by slow addition of Et3N (2.74 mmol, 0.38 mL). The
solution was stirred for 1 h and then concentrated. The residue
was dissolved in EtOAc (50 mL), and the mixture was washed
3× with water and once with brine. The solution was dried
over MgSO4, filtered, and evaporated onto silica gel. The
product was purified by flash chromatography (EtOAc, Rf )
0.3) to give 0.69 g (80%) of 16 as an oil. IR (thin film): 2983,
1
2832, 1695, 1608, 1518, 1254, 831 cm-1. H NMR (CDCl3): δ
7.59 (2H, d, J ) 9 Hz), 6.91 (2H, d, J ) 9 Hz), 4.91-4.81 (1H,
m), 3.83 (3H, s), 3.40 (1H, dd, J ) 10.2, 16.8 Hz), 3.23 (1H,
dd, J ) 6, 14.1 Hz), 3.19 (1H, dd, J ) 6.3, 14.1 Hz), 3.06 (1H,
dd, J ) 6.9, 16.5 Hz), 2.61 (q, 2H, J ) 7.8 Hz), 1.18 (3H, t, J
) 7.8 Hz). 13C NMR: δ 199.42, 160.97, 155.83, 128.16, 121.75,
114.05, 79.17, 55.38, 39.65, 37.49, 32.63, 9.77. FAB MS (M +
H): 280. Anal. (C14H17NO3S) C, H, N.
1
1609, 1517, 1306, 1255, 1022, 972 cm-1. H NMR (CDCl3): δ
7.60 (2H, d, J ) 9 Hz), 6.91 (2H, d, J ) 9 Hz), 4.83 (1H, ddd,
J ) 2.1, 10.2, 11.7), 4.28-4.18 (4H, m), 3.83 (3H, s), 3.63 (1H,
dd, J ) 10.2, 23.7 Hz), 3.63 (1H, dd, J ) 11.7, 22.2 Hz), 1.36
(3H, t, J ) 7.2 Hz), 1.32 (3H, t, J ) 7.2 Hz). 13C NMR: δ 161.19,
155.68 (d, J ) 6 Hz), 128.38, 120.90, 114.11, 74.86 (d, J ) 168
Hz), 63.57 (d, J ) 6.9 Hz), 63.16 (d, J ) 6.6 Hz), 55.37, 37.99,
16.59, 16.52. 31P NMR: δ 19.64. FAB MS (M + H): 314. Anal.
(C14H20NO5P) C, H, N.
[3-(4-Met h oxyp h en yl)-4,5-d ih yd r oisoxa ol-5-yl]m et h -
a n eth iol (23). Thioester 22 (75 mg, 0.27 mmol) was stirred
in 4 mL of methanol. NaOH (1M in H2O, 0.27 mL, 0.27 mmol)
was added followed by 1 mL of water. The white precipitate
that was formed after it was stirred overnight was filtered
giving 19 mg (32%) of the thiol; mp 185 °C (dec). IR (Nujol):
1
1610, 1518, 1461, 1376, 1253, 829 cm-1. H NMR (DMSO-d6):
δ 7.59 (2H, d, J ) 9 Hz), 6.98 (2H, d, J ) 9 Hz), 4.96-4.85
(1H, m), 3.78 (3H, s), 3.55 (1H, dd, J ) 10.5, 17.1 Hz), 3.22
(1H, dd, J ) 6.9, 17.1 Hz), 3.14-2.99 (2H, m). 13C NMR: δ
160.40, 155.80, 128.01, 114.05, 78.74, 55.24, 42.40. FAB MS
(M + H): 224. Anal. (C11H13NO2S) C, H, N.
[3-(4-Meth oxyp h en yl)-4,5-d ih yd r o-isoxa zol-5-yl]p h os-
p h on ic Acid (17). Phosphonate ester 16 (0.25 g, 0.80 mmol)
was dissolved in 15 mL of CH2Cl2. Bromotrimethylsilane (0.34
mL, 6.4 mmol) was added, and the solution was stirred for 3
d at room temperature. The reaction was quenched by addition
of 1 mL of water, and the mixture was stirred for 20 min. The
solution was concentrated and made basic by the addition of
saturated NaHCO3. The solution was evaporated and dissolved
in a minimal amount of water. Concentrated HCl was added
to acidify the solution. The white precipitate that formed was
filtered and dried to give 121 mg (59%) of 17; mp 238-240 °C.
IR (Nujol): 2775, 2356, 1610, 1516, 1459, 1376, 1180, 1040
cm-1. 1H NMR (DMSO-d6): δ 8.4 (2H, bs), 7.59 (2H, d, J ) 8.4
Hz), 6.98 (2H, d, J ) 8.7 Hz), 4.62 (1H, t, J ) 11.4 Hz), 3.78
(3H, s), 3.74-3.57 (1H, m), 3.47-3.30 (1H, m). 13C NMR: δ
160.49, 155.42, 128.17, 121.17, 114.15, 75.6 (d, J ) 162 Hz),
55.31, 37.31. FAB MS (M - H): 256. HRMS m/z calcd for
(R*,R*)-3-(4-Meth oxy-p h en yl)-5-th iir a n yl-4,5-d ih yd r o-
isoxa zole (25a ). (R*,R*)-3-(4-Methoxy-phenyl)-5-oxiranyl-4,5-
dihydro-isoxazole (24a , 0.05 g, 0.23 mmol) was dissolved in
1 mL of MeOH. Thiourea (17 mg, 0.23 mmol) was added, and
the suspension was heated to 80 °C for 5 h in a pressure tube.
After it was cooled, the solution was partitioned between 10
mL each of DCM and H2O. The organic layer was dried over
MgSO4 and evaporated to give 57 mg of a white solid (100%);
mp 125-128 °C. IR (Nujol): 1610, 1597, 1518, 1464, 1253,
1
1180 cm-1. H NMR (CDCl3): δ 7.60 (2H, d, J ) 9.3 Hz), 6.92
(2H, d, J ) 9.3 Hz), 4.88 (1H, ddd, J ) 5.1, 6.6, 10.5 Hz), 3.84
(3H, s), 3.40 (1H, dd, J ) 10.5, 16.8 Hz), 3.19 (1H, dt, J ) 5.7,
6.3 Hz), 3.13 (1H, dd, J ) 6.6, 16.8 Hz), 2.47 (1H, dd, J ) 1.5,
6.3 Hz), 2.30 (1H, dd, J ) 1.5, 5.4 Hz). 13C NMR δ. FAB MS
(M + H): 236. Anal. (C12H14NO2S) C, H, N.
C
10H11NO5P, 256.0375; found, 256.0381. Anal. (C10H12NO5P)
C, H, N.
Met h yl-vin yl-p h osp h in ic Acid 2-Ch lor o-et h yl E st er
(19). Methyl dichlorophosphine (0.5× g, 4.3 mmol) was stirred
in 25 mL of dry ether under N2. To this solution was added
0.58 mL (8.6 mmol) of 2-chloroethanol followed by 1.7 mL (22
mmol) of pyridine. The solution was stirred overnight, filtered,
and evaporated to give a clear oil. The oil was heated under
N2 in a pressure tube to 160 °C for 3 h. The reaction was
allowed to cool, and 0.65 mL (4.7 mmol) of Et3N was added.
The vessel was sealed and heated to 120 °C for 2 h. The residue
was purified by Kugelrohr distillation (160 °C, 2 Torr) to give
0.335 g (47%) of an oil identical to the known compound.47
(R*,S*)-3-(4-Meth oxy-p h en yl)-5-th iir a n yl-4,5-d ih yd r o-
isoxa zole (25b). (R*,S*)-3-(4-Methoxy-phenyl)-5-oxiranyl-4,5-
dihydro-isoxazole (24b, 82 mg, 0.37 mmol) was treated exactly
as above (25a ) to give 78 mg (100%) of a while solid; mp 127-
130 °C. IR (Nujol): 1611, 1597, 1519, 1457, 1255, 1179 cm-1
.
1H NMR (CDCl3): δ 7.61 (2H, d, J ) 8.7 Hz), 6.92 (2H, d, J )
8.7 Hz), 4.32 (1H, ddd, J ) 6.9, 8.1, 10.5 Hz), 3.84 (3H, s),
3.49 (1H, dd, J ) 10.2, 16.5 Hz), 3.33 (1H, dd, J ) 6.9, 16.5
Hz), 3.13 (1H, ddd, J ) 5.1, 6.0, 8.1 Hz), 2.62 (1H, dd, J ) 1.8,
6.0 Hz), 2.37 (1H, dd, J ) 1.8, 5.4 Hz). 13C NMR: δ 161.32,
156.08, 128.49, 121.91, 114.38, 85.37, 55.69, 40.63, 36.24,
25.06. FAB MS (M + H): 236. Anal. (C12H13NO2S) C, H, N.
Meth yl-[3-(4-m eth oxyp h en yl-4,5-d ih yd r o-isoa zol-5-yl)-
p h osp h in ic Acid 2-Ch lor o-eth yl Ester (20). Chloro-oxime