Synthesis of 2-Oxazolone-4-carboxylates
J . Org. Chem., Vol. 67, No. 4, 2002 1107
mmol) to provide oxazolone 1d as a white crystalline solid
(0.720 g, 68% without p-TSA or 0.80 g, 75% with p-TSA).
5-Isop r op yl-4-ca r boeth oxy-4-oxa zolin -2-on e (1e). Using
method C, ethyl 4-methyl-3-[(p-nitrobenzenesulfonyl)oxy]-2-
oxopentanoate (2e, 1.42 g, 3.95 mmol) was condensed with
methyl carbamate (1.50 g, 20.0 mmol) and p-toluenesulfonic
acid monohydrate (0.080 g, 0.40 mmol) in 80 mL of toluene.
The reaction was run for 48 h, and fresh methyl carbamate
was added midway through the reaction. Oxazolone 1e was
obtained as a white crystalline solid (0.320 g, 41%): mp 123-
125 °C; 1H NMR (400 MHz, CDCl3) δ 1.24 (d, J ) 7.9 Hz, 6H),
1.36 (t, J ) 7.1 Hz, 3H), 3.54 (m, J ) 7.0, 1H), 4.36 (q, J ) 7.1
Hz, 2H), 8.81 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 14.2, 20.0,
25.8, 61.5, 112.5, 154.0, 154.5, 158.9; IR (KBr) 3199, 1762,
1720, 1669 cm-1. Anal. Calcd for C9H13NO4: C, 54.26; H, 6.58;
N, 7.03. Found: C, 54.29; H, 6.38; N, 7.10.
(MgSO4), and filtered, and the filtrate was evaporated under
reduced pressure. The product was triturated with EtOAc/
hexanes to provide the alcohol 14a as a white solid (0.20 g,
1
98%): mp 210-212 °C; H NMR (400 MHz, (CD3)2CO) δ 3.65
(s, 2H), 4.12 (t, J ) 5.6 Hz, 1H), 4.31 (d, J ) 5.6 Hz, 2H), 7.13
(m, 5H), 9.12 (br s, 1H); 13C NMR (100 MHz, (CD3)2CO) δ 30.4,
53.0, 122.1, 126.8, 128.67, 128.74, 135.5, 137.8, 155.4; IR (KBr)
3256 (br), 3100-2850 (br), 1750, 1719, 1700 cm-1
.
5-Isobu tyl-4-h yd r oxym eth yl-4-oxa zolin -2-on e (14d ). By
the same procedure 5-isobutyl-4-carboethoxy-4-oxazolin-2-one
(1d , 0.21 g, 1.0 mmol) was reduced with DIBAL-H (1.5 M in
toluene, 2.5 mL, 3.8 mmol). Alcohol 14d was obtained as a
white solid following recrystallization from EtOAc/hexanes
(0.17 g, 100%): mp 70-71 °C; 1H NMR (200 MHz, (CD3)2CO)
δ 1.03 (d, J ) 6.6 Hz, 6H), 1.98 (m, 1H), 2.41 (d, J ) 7.0 Hz,
2H), 4.30 (t, J ) 5.3 Hz, 1H), 4.46 (d, J ) 4.4 Hz, 2H), 9.36 (br
s, 1H); 13C NMR (100 MHz, (CD3)2CO) δ 21.7, 27.3, 33.1, 52.9,
122.0, 136.2, 155.6; IR (KBr) 3380, 3269, 3130, 2959-2850,
Using method D, ethyl 3-bromo-4-methyl-2-oxopentanoate
(4e, 0.95 g, 4.00 mmol) was reacted with methyl carbamate
(1.50 g, 20.0 mmol) and AgOTf (1.03 g, 4.00 mmol) to provide
oxazolone 1e as a white crystalline solid (0.110 g, 14% for a
reaction time of 24 h, and 0.24 g, 30% for a reaction time of
48 h).
1752, 1700, 1650 cm-1
.
4-Hyd r oxym eth yl-2-oxa zolid in on e (15b). By the same
procedure, 4-carboethoxy-4-oxazolin-2-one (1b, 0.31 g, 2.0
mmol) was reduced with DIBAL-H (1.5 M in toluene, 5.0 mL,
7.5 mmol) for 30 min. Over-reduced oxazolidinone 15b was
obtained as a white solid following recrystallization from
EtOAc/hexanes (0.030 g, 13%): 1H NMR (200 MHz, (CD3)2-
SO) δ 2.50 (s, 1H), 3.77 (d, J ) 11.8 Hz, 1H), 3.95 (d, J ) 12.1
Hz, 1H), 4.09 (d, J ) 9.9 Hz, 1H), 4.17 (d, J ) 9.2 Hz, 1H),
4.26 (m, 1H), 9.45 (s, 1H); 13C NMR (100 MHz, (CD3)2CO) δ
65.0, 70.6, 84.2, 157.4.
5-Meth yl-4-ca r boeth oxy-4-oxa zolin -2-on e (1f). Using
method C, ethyl 3-[(p-nitrobenzenesulfonyl)oxy]-2-oxobu-
tanoate (2f, 1.33 g, 4.00 mmol) was condensed with methyl
carbamate (1.50 g, 20.0 mmol) and p-toluenesulfonic acid
monohydrate (0.080 g, 0.400 mmol) in 80 mL of toluene to
provide oxazolone 1f as a white crystalline solid (0.380 g,
1
56%): mp 130-132 °C; H NMR (400 MHz, CDCl3) δ 1.36 (t,
J ) 7.1 Hz, 3H), 2.41 (s, 3H), 4.34 (q, J ) 7.1 Hz, 2H), 8.69 (br
4-Ca r boxy-5-ben zyl-4-oxa zolin -2-on e (16a ). To a solution
of 4-carboethoxy-5-benzyl-4-oxazolin-2-one (1a , 1.00 g, 4.04
mmol) in THF (5 mL) and H2O (5 mL) was added NaOH (1.00
g, 25 mmol) The mixture was stirred at rt for 24 h. The
reaction mixture was acidified with 1 N HCl to pH 3 and
extracted with EtOAc. The EtOAc extracts were washed with
H2O and brine, dried (MgSO4), and evaporated in vacuo.
Trituration of the residue with EtOAc/hexanes provided the
s, 1H); 13C NMR (100 MHz, CDCl3) δ 11.9, 14.2, 61.6, 114.4,
146.5, 153.8, 158.9; IR (KBr) 3200, 1762, 1717, 1675 cm-1
.
Anal. Calcd for C7H9NO4: C, 49.12; H, 5.3; N, 8.18. Found:
C, 49.04; H, 5.46; N, 8.13.
Using method D, ethyl 3-bromo-2-oxobutanoate (4f, 0.840
g, 4.00 mmol) was reacted with methyl carbamate (1.50 g, 20.0
mmol) and AgOTf (1.03 g, 4.00 mmol) [with or without
p-toluenesulfonic acid monohydrate (0.080 g, 0.400 mmol)] to
provide oxazolone 1f as a white crystalline solid (0.410 g, 60%
with or without TSA).
1
acid 16a as a white solid (0.870 g, 98%): mp 210-212 °C; H
NMR (200 MHz, (CD3)2CO) δ 4.28 (s, 2H), 7.38 (m, 5H), 9.95
(br s, 1H); 13C NMR (100 MHz, (CD3)2CO) δ 31.6, 115.1, 127.2,
128.9, 136.6, 147.7, 153.3, 159.7; IR (KBr) 3500-2500 (br),
5-P h en yl-4-ca r boeth oxy-4-oxa zolin -2-on e (1g). Using
method C, ethyl 3-[(p-nitrobenzenesulfonyl)oxy]-2-oxo-3-phen-
ylpropanoate (2g, 1.57 g, 4.00 mmol) was condensed with
methyl carbamate (1.50 g, 20.0 mmol) and p-toluenesulfonic
acid monohydrate (0.080 g, 0.400 mmol) in 80 mL of toluene
to provide oxazolone 1g as a white crystalline solid (0.520 g,
1741, 1710, 1650 cm-1
.
4-Ca r boxy-4-oxa zolin -2-on e (16b). By the same proce-
dure, 4-carboethoxy-4-oxazolin-2-one (1b, 1.00 g, 6.36 mmol)
in THF (5 mL) and H2O (5 mL) was treated with NaOH (1.00
g, 25 mmol). The acid 16b was obtained as a white solid
following trituration with EtOAc/hexanes (0.700 g, 85%): mp
200-201 °C; 1H NMR (200 MHz, (CD3)2CO) δ 7.72 (d, J ) 1.2,
1H), 10.12 (br s, 1H), 11.00 (br s, 1H); 13C NMR (100 MHz,
(CD )2CO ) δ 120.7, 135.2, 154.6, 158.9; IR (KBr) 3500-2500
1
46%): mp 162-164 °C; H NMR (400 MHz, CDCl3) δ 1.39 (t,
J ) 7.1 Hz, 3H), 4.39 (q, J ) 7.1 Hz, 2H), 7.45 (m, 3H), 8.03
(m, 2H), 9.22 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 62.0, 113.7,
126.0, 127.9, 128.4, 130.5, 145.9, 153.3, 158.3; IR (KBr) 3187,
1768, 1720, 1630 cm-1. Anal. Calcd for C12H11NO4: C, 61.8;
H, 4.75; N,
3
3
(br), 1757, 1700, 1650 cm-1
.
4-Ca r boxy-5-isobu tyl-4-oxa zolin -2-on e (16d ). By the
same procedure, 4-carboethoxy-5-isobutyl-4-oxazolin-2-one (1d ,
0.50 g, 2.3 mmol) in THF (5 mL) and H2O (5 mL) was treated
with NaOH (0.50 g, 13 mmol). The acid 16d was obtained as
Using method D, ethyl 3-bromo-2-oxo-3-phenylpropanoate
(4g, 1.08 g, 4.00 mmol) was reacted with methyl carbamate
(1.50 g, 20.0 mmol) and AgOTf (1.03 g, 4.00 mmol) to provide
oxazolone 1g as a white crystalline solid (0.600 g, 64%).
5-Car bom eth oxy-4-car bom eth oxy-4-oxazolin -2-on e (1h ).
Using method D, methyl 4-carbomethoxy-3-bromo-2-oxobu-
tanoate (4h , 1.52 g, 6.00 mmol) was reacted with methyl
carbamate (2.25 g, 30.0 mmol), AgOTf (1.54 g, 6.00 mmol), and
p-toluenesulfonic acid monohydrate (0.110 g, 0.60 mmol) to
provide oxazolone 1h as a white crystalline solid (0.630 g,
49%): mp 93-95 °C; 1H NMR (200 MHz, CDCl3) δ 3.76 (s,
3H), 3.88 (s, 2H), 3.89 (s, 3H), 8.54 (br s, 1H); 13C NMR (100
MHz, CDCl3) δ 31.8, 52.6, 52.8, 116.3, 141.9, 153.3, 158.6,
167.5; IR (KBr) 3216, 2965, 1760 (br), 1710, 1670 cm-1. Anal.
Calcd for C8H9NO6: C, 44.66; H, 4.22; N, 6.51. Found: C,
44.84; H, 4.19; N, 6.49.
5-Benzyl-4-hydroxymethyl-4-oxazolin-2-one (14a).DIBAL-H
(1.5 M in toluene, 2.5 mL, 3.8 mmol) was added dropwise to a
solution of 5-benzyl-4-carboethoxy-4-oxazolin-2-one (1a , 0.25
g, 1.0 mmol) in dry CH2Cl2 (2.5 mL) at 0 °C under N2. The
reaction mixture was stirred for 4 h at 0 °C and then poured
into ice-cooled 2 M HCl (15 mL). The product was extracted
with EtOAc, the EtOAc extracts were washed with brine, dried
1
a white solid (0.43 g, 100%): mp 212-213 °C; H NMR (200
MHz, (CD3)2CO) δ 1.13 (d, J ) 6.8 Hz, 6H), 2.17 (m, 1H), 2.86
(d, J ) 7.1 Hz, 2H), 9.88 (br s, 1H); 13C NMR (100 MHz, (CD3)2-
CO 3) δ 21.8, 27.6, 34.3, 115.5, 149.0, 153.5, 159.8; IR (KBr)
3500-2500 (br), 2954, 1736, 1700, 1650 cm-1
.
4-Ca r boxy-5-ben zyl-4-oxa zolin -2-on yl-L-a la n in e Meth -
yl Ester (18a a ). To a stirred solution of 4-carboxy-5-benzyl-
4-oxazolin-2-one (16a , 0.22 g, 1.0 mmol) and L-Ala‚OMe‚HCl
(17a , 0.14 g 1.0 mmol) in CH2Cl2 (10 mL) were added Et3N
(0.14 mL, 0.11 g, 1.1 mmol) and 1-ethyl-3-[3-(dimethylamino)-
propyl]carbodiimide hydrochloride (EDCI‚HCl, 0.21 g, 1.1
mmol). The mixture was stirred for 12 h at rt. The mixture
was then washed with H2O (2 × 10 mL) and brine (10 mL),
dried (MgSO4), filtered, and concentrated under reduced
pressure. The residue was chromatographed on a silica gel
column, eluting with EtOAc/hexanes (1:1) and recrystallized
from EtOAc/hexanes to provide the dipeptide analogue 18a a
as a white solid (0.23 g, 76%): mp 116-118 °C; 1H NMR (200
MHz, CDCl3) δ 1.42 (d, J ) 7.3 Hz, 3H), 3.71 (s, 3H), 4.12 (d,
J ) 15.2 Hz, 1H), 4.28 (d, J ) 15.2 Hz, 1H), 4.63 (m, J ) 7.3