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Notes
J . Org. Chem., Vol. 64, No. 25, 1999 9299
Sch em e 3. P r ep a r a tion of Resin 8a
a
(a) NaH, HCtCCH2Cl, THF/DMF (10:1), rt; (b) aq HCl; then aq NaOH; (c) (Boc)2O, CH2Cl2, rt; (d) aq NaOH; then aq HCl; (e) PS-
O(CH2)3OH, DIC, DMAP, CH2Cl2/DMF (4:1).
1.25 (t, 3H, J ) 7.1 Hz); 13C NMR (75 MHz, CDCl3) δ 179.7,
171.4, 136.1, 131.8, 129.6, 126.6, 124.4, 119.0, 61.3, 56.6, 36.0,
13.9.
CDCl3) δ 5.47 (d, 1H, J ) 8.0 Hz), 4.35 (m, 1H), 4.14 (m, 2H),
2.65 (m, 2H), 2.02 (t, 1H, J ) 2.4 Hz), 1.37 (s, 9H), 1.21 (t, 3H,
J ) 7.1 Hz); 13C NMR (75 MHz, CDCl3) δ 170.2, 154.8, 79.6,
78.5, 71.3, 61.2, 52.0, 28.0, 22.4, 13.8.
Eth yl 2-[(P h en ylam in o)car bon ylam in o]pen t-4-en oate (6)
fr om 1. Ethyl 2-aminopent-4-enoate 1 (0.2 g, 1.39 mmol) was
treated with phenyl isocyanate (0.165 g, 1.39 mmol) in CH2Cl2
(10 mL) for 2 h at ambient temperature. The solvent was
removed at reduced pressure. Column chromatography (silica
gel, EtOAc:hexane ) 1:4) of the residue afforded the desired
compound 6 (0.346 g, 1.32 mmol, 95%) as a white solid: mp 233-
2-[(ter t-Bu toxy)ca r bon yla m in o]p en t-4-yn oic a cid (17).
To a solution of 16 (5 g, 20.7 mmol) in EtOH/H2O (20 mL/20
mL) was added NaOH (1.66 g, 41.5 mmol) at 0 °C. The reaction
mixture was stirred overnight at room temperature, extracted
with ether (30 mL x 3), and dried with anhydrous MgSO4.
Removal of the solvent under reduced pressure followed by the
recrystallization (EtOAc and hexane) afforded 17 (3.6 g, 15.90
mmol, 81%) as a white solid: Mp 97-98 °C; FTIR (neat) 3330,
235 °C; FTIR (KBr) 3207, 2983, 1740, 1652, 1553, 1497 cm-1
;
1H NMR (300 MHz, CDCl3) δ 7.82 (s, 1H), 7.37-7.17 (m, 4H),
6.97 (t, 3H, J ) 7.2 Hz), 6.18 (d, 1H, J ) 7.8 Hz), 5.75-5.66 (m,
1H), 5.11-5.04, (m 2H), 4.62 (dd, 1H, J ) 13.4, 6.4 Hz), 4.21-
4.10 (m, 2H), 2.59-2.46 (m, 2H), 1.22 (t, 3H, J ) 7.1 Hz); 13C
NMR (75 MHz, CDCl3) δ 172.5, 155.8, 138.7, 132.4, 128.6, 122.6,
119.7, 118.5, 61.1, 52.4, 36.6, 13.9.
1
2979, 1708, 1509 cm-1; H NMR (300 MHz, CDCl3) δ 11.98 (s,
1H), 5.42 (s, br, 1H), 4.53 (m, 1H), 2.79 (m, 2H), 2.08 (s, 1H),
1.46 (S, 9H); 13C NMR (75 MHz, CDCl3) δ 175.0, 155.4, 80.7,
78.3, 71.9, 51.8, 28.3, 22.5. Anal. Calcd for C10H15NO4: C, 56.32;
H, 7.09; N, 6.56. Found: C, 56.40; H, 7.12; N, 6.54.
Eth yl 2-[(P h en ylam in o)car bon ylam in o]pen t-4-en oate (6)
fr om 2. To a solution of thiourea 2 (0.3 g, 1.07 mmol) in THF
(20 mL) was added phenyl isocyanate (0.256 g, 2.15 mmol),
R-nitrotoluene (0.146 g, 1.07 mmol), and Et3N (10 mg, 0.10
mmol). The reaction mixture was stirred for 10 h at room
temperature and then refluxed overnight. The solvent was
removed under reduced pressure and the residue purified by
column chromatography (silica gel, EtOAc:hexane ) 1:9) to give
6 (0.151 g, 0.57 mmol, 54%) as a white solid (see data in
preceding paragraph).
Gen er a l P r oced u r e for th e Syn th esis of Th ioh yd a n toin s
12a -r (12j). A solution of DMAP (0.195 g, 1.6 mmol) in DMF/
CH2Cl2 (6 mL/24 mL) was prepared. Acid 17 (3.4 g, 16 mmol)
and DIC (2.01 g, 16 mmol) were dissolved in DMF/CH2Cl2 (6
mL/24 mL), and this solution was added to the flask which
contained the hydroxypropyloxymethylpolystyrene resin (4 g, 8
mmol). Finally, the DMAP solution was added, and the reaction
mixture was stirred overnight at ambient temperature. The resin
was washed with DMF, CH2Cl2, and ether and dried to give the
resin 8.
Eth ly 2-Am in op en t-4-yn oa te (15). To the solution of ben-
zophenone Schiff base 13 (5 g, 18.70 mmol) in THF/DMF (60
mL/15 mL) was added NaH (0.49 g, 20.57 mmol) under nitrogen.
The reaction mixture was stirred for 10 min, followed by the
addition of propargyl chloride (1.41 g, 18.70 mmol), and stirred
for 8 h at ambient temperature. Ethyl acetate (100 mL) was
added to the reaction mixture, which was washed with water
(30 mL × 3) and dried with anhydrous MgSO4. Removal of
solvent under reduced pressure gave 5.25 g of crude unstable
intermediate 14.
Resin 8 (4 g) was swollen in THF (100 mL), and R-nitrotoluene
(3.29 g, 24 mmol), phenyl isocyanate (5.71 g, 48 mmol), and Et3N
(0.12 mL) were added. The reaction mixture was stirred at 60
°C overnight and then washed with DMF, THF, and ether.
Drying in vacuo gave resin 9 (R1 ) Ph) which was treated with
50% TFA/CH2Cl2(30 mL) at ambient temperature for 1 h. The
resin was washed with DMF and CH2Cl2, followed by treatment
with 10% Et3N in CH2Cl2 (30 mL) for 1 h. The resulting resin
was washed with DMF, CH2Cl2, and ether and dried under
vacuum to give the free amine functional group attached resin.
This resin (0.2 g scale) was treated with the benzaldehyde
(0.195 g, 1.8 mmol) in TMOF/THF (5 mL/5 mL) for 2 h at
ambient temperature and then washed with TMOF/THF (1:1).
Subsequent addition of NaCNBH3 (48 mg, 0.76 mmol) in THF/
MeOH/AcOH (9 mL/1 mL/0.1 mL) and agitating overnight at
ambient temperature, followed by washes with MeOH/THF (1:
3), MeOH/DMF (1:3), DMF, and CH2Cl2, gave resin 10 which
was dried under nitrogen.
Resin 10 was treated with phenyl isothiocyanate (0.162 g, 1.2
mmol) in THF (10 mL) at 60 °C overnight to sequentially effect
thiourea formation (giving 11) and cycloelimination to produce
isoxazolothiohydantoin 12j. The resin was washed with THF,
and the combined organic solvent was evaporated under reduced
pressure. The resulting residue was purified by short-pass
column chromatography (Rf values: phenyl isothicyanate, 0.95;
product, 0.05 in hexane) to give 52 mg of 12j.
A solution of 14 in THF (50 mL) was treated with 1 N HCl to
adjust the pH to ≈4 and stirred for 5 min. Ethyl acetate (50
mL) and water (30 mL) were added to the reaction mixture, and
the aqueous layer was neutralized with 1 N NaOH (pH ≈9) and
extracted with ethyl acetate (20 mL x 5). The organic layer was
dried with anhydrous MgSO4. Removal of solvent under reduced
pressure, followed by column chromatography (silica gel, EtOAc:
hexane ) 1:5), afforded 15 (1.97 g, 14.02 mmol, 75%) as a yellow
oil: FTIR (neat) 3382, 3290, 2980, 1729, 1192 cm-1
;
1H NMR
(300 MHz, CDCl3) δ 4.24-4.17 (m, 2H), 3.61 (t, 1H, J ) 5.5 Hz),
2.62 (ddd, 1H, J ) 5.5, 2.5, 2.5 Hz), 2.11 (t, 1H, J ) 2.5 Hz),
1.31 (t, 3H, J ) 7.1 Hz); 13C NMR (75 MHz, CDCl3) δ 173.2,
79.4, 70.7, 60.7, 52.9, 24.5, 13.8.
Eth yl 2-[(ter t-Bu toxy)car bon ylam in o]pen t-4-yn oate (16).
To a solution of 15 (3 g, 21.27 mmol) in CH2Cl2 (50 mL) was
added di-tert -butyl dicarbonate (4.64 g, 21.27 mmol) at 0 °C,
and the reaction mixture was stirred overnight at room tem-
perature. Removal of solvent under reduced pressure and short-
pass column chromatography (silica gel, EtOAc:hexane ) 1:5)
afforded 16 (4.71 g, 19.54 mmol, 92%) as a colorless oil: FTIR
4-[(3,4-Dim eth oxyp h en yl)m eth yl]-3-[(3-eth ylisoxa zol-5-
yl)m eth yl]-1-ph en yl-5-th ioxopyr r olidin -2-on e (12d). Mp 111-
112 °C; FTIR (KBr) 3008, 2965, 1751, 1603, 1464 cm-1; 1H NMR
(300 MHz, CDCl3) δ 7.51-7.42 (m, 3H), 7.23-7.20 (m, 2H), 6.96
(d, 1H, J ) 1.5 Hz), 6.89-6.82 (m, 2H), 5.85 (s, 1H), 5.66 (d, 1H,
1
(neat) 3308, 2979, 1719, 1500, 1158 cm-1; H NMR (300 MHz,