900
M. Cox et al.
chromatography (dichloromethane/ethyl acetate) to give the oxazole
above (167 mg, 46%), and the acetamide of phthalimidylalanine (13)
(11 mg, 4%), mp 145–153◦C (lit.[21] 135–137◦C) (Found (Electro-
Afterevaporation, theresiduewasstirredwith1.5 Maqueoushydrochlo-
ric acid (10 mL) for 20 min at ambient temperature. Dichloromethane
(10 mL) was added, the mixture was filtered, and the organic layer
was discarded. The aqueous layer was extracted once more with
dichloromethane (10 mL) and then evaporated to dryness. The title
compound was isolated as a yellow oil, which crystallized on stand-
ing as rosettes (185 mg, 67%). A sample was recrystallized from
ethanol/diethyl ether, mp 114–116◦C (Found: C 40.5, H 4.4, N 13.7%;
M+•, 170.0693. C7H11ClN2O3 requires C 40.7, H 4.1, N 13.6%;
M+•, 170.0691). νmax/cm−1 3400, 1732, 1614, 1556, 1146, 1021.
δH (D2O/CD3OD) 7.94 (1 H, s), 4.95 (3 H, br s), 4.57 (2 H, s), 4.45 (2 H,
q, J 7.2), 1.42 (3 H, t, J 7.2). δC (D2O/CD3OD) 159.2, 157.3, 142.8,
•
spray MS): [M + Na]+ , 283.1; [M + H]+•, 261.2. C13H12N2O6 requires
•
[M + Na]+ , 283.2; [M + H]+•, 261.2). νmax/cm−1 3255, 3173, 1782,
1740, 1718, 1523, 1240, 1199, 1100, 1087. δH 9.00 (1 H, br s, NH
exchangeable), 7.87 (2 H, m), 7.77 (2 H, m), 5.00 (1 H, q, J 7.2), 2.30
(3 H, s), 1.67 (3 H, d, J 7.2). δC 173.4, 169.0, 167.6, 134.5, 132.0, 123.7,
49.5, 25.0, 14.6.
Ethyl 2-[(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-
1,3-oxazole-5-carboxylate (18)
•
132.9, 61.5, 35.0, 12.3. m/z 170 (77%, M+ ), 125 (18), 69 (100).
The isoxazolone (16) (1.820 g, 5.29 mmol) was irradiated in acetone
(900 mL) for 3 h as described above. The solvent was then removed
under reduced pressure and the solid residue was suspended in hot
ethanol (70 mL), cooled on ice, then diluted with water (30 mL). The
product was collected by filtration as a slightly yellow powder (1.390 g,
88%), mp 169–170◦C (sublimation at 160–169◦C). A sample was
Ethyl 2-(Aminomethyl)-4-methyl-1,3-oxazole-5-carboxylate
Hydrochloride (9)
A suspension of the phthalimide (19) (2.27 g, 7.24 mmol) and hydrazine
hydrate (460 mg, 9.00 mmol) in ethanol (45 mL) was stirred for 3.5 h at
65◦C. After evaporation, the residue was stirred with 1.5 M aqueous HCl
(20 mL) for 20 min at ambient temperature. Dichloromethane (20 mL)
was added, the mixture was filtered, and the organic layer was discarded.
The aqueous layer was extracted once more with dichloromethane
(10 mL) and then evaporated to dryness, azeotroping with toluene
(2 × 3 mL). The residue was suspended in hot dichloromethane (30 mL)
and then cooled on ice. After addition of diethyl ether (15 mL) and cool-
ing overnight, the product (9) was collected as light-yellow, lustrous
recrystallized from ethanol/water (Found: C 59.8, H 4.1, N 9.3%;
•
M+•, 300.0745. C15H12N2O5 requires C 60.0, H 4.0, N 9.3%; M+
,
300.0746). νmax/cm−1 1771, 1732, 1719, 1544, 1422, 1395, 1148. δH
7.92 (2 H, m), 7.77 (2 H, m), 7.65 (1 H, s), 5.05 (2 H, s), 4.37 (2 H,
q, J 7.1), 1.37 (3 H, t, J 7.1). δC 167.1, 161.3, 157.3, 143.3, 134.3,
134.0, 131.9, 123.8, 61.5, 34.8, 14.2. m/z 300 (71%, M+•), 255 (6,
[M – OC2H5]+•), 160 (100).
crystals (1.23 g, 77%), mp 100–108◦C (Found: C 43.1, H 6.2, N 12.5%;
Ethyl 2-[1-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-
1,3-oxazole-5-carboxylate (21)
•
M+•, 184.0843. C8H13ClN2O3 requires, C 43.5, H 5.9, N 12.7%; M+
,
184.0848). νmax/cm−1 3423, 3108, 1712, 1616, 1577, 1507, 1338, 1107.
δH (CDCl3/[D6]DMSO) 8.90 (3 H, br s), 4.36 (2 H, q, J 7.2), 4.25 (2 H,
br s), 2.46 (3 H, s), 1.38 (3 H, t, J 7.2). δC (CDCl3/[D6]DMSO) 158.5,
158.1, 145.5, 138.6, 61.2, 36.0, 14.1, 13.1. m/z 184 (55%, M+•), 156
(15), 139 (13), 83 (100).
The isoxazolone (14) (159 mg, 0.444 mmol) was irradiated in acetone
(200 mL) for 2 h as described above. The crude residue was passed
through a short plug of silica using dichloromethane as eluent to give
the title compound as a colourless oil, which solidified on stand-
ing as iridescent crystals (99 mg, 71%). A sample was recrystallized
from dichloromethane/hexane, mp 96–100◦C, [α]D −6.4◦ [(S)-isomer,
c 1.093 in CHCl3] (Found: C 61.2, H 4.6, N 8.6%; M+•, 314.0900.
C16H14N2O5 requires C 61.1, H 4.5, N 8.9%; M+•, 314.0903).
νmax/cm−1 1779, 1694, 1614, 1587, 1535, 1303, 1157, 1074, 1019.
δH 7.87 (2 H, m), 7.76 (2 H, m), 7.70 (1 H, s), 5.62 (1 H, q, J 7.1), 4.35
(2 H, q, J 7.1), 1.95 (3 H, d, J 7.1),1.35 (3 H, t, J 7.1). δC 167.0, 164.6,
157.4, 143.0, 134.2, 133.9, 131.6, 123.5, 61.2, 43.3, 15.8, 13.9. m/z 314
(27%, M+•), 174 (100).
Ethyl 2-(1-Aminoethyl)-4-methyl-1,3-oxazole-5-carboxylate
Hydrochloride (22)
A mixture of (20) (150 mg, 0.457 mmol) and hydrazine hydrate (27 µL,
0.555 mmol) in ethanol (6 mL) was reacted as described above to
give the product (22) as a colourless oil (62 mg, 58%) (Found:
[M + H]+•, 199.1080. C9H14N2O3 requires [M + H]+•, 199.1083). νmax
(film)/cm−1 3400br, 1716, 1651. δH (CDCl3) 9.20 (3 H, br s), 4.92 (1 H,
br s), 4.33 (2 H, br s), 2.40 (3 H, s), 1.89 (3 H, br s), 1.36 (3 H, br s). δC
(CDCl3) 161.6, 158.6, 145.7, 138.6, 61.4, 45.4, 17.4, 14.0, 13.1.
(S)-Ethyl 2-[2-(4-Benzyloxyphenyl)-1-phthalimidoethyl]oxazole-
5-carboxylate (24)
Ethyl 2-(1-Aminoethyl)-1,3-oxazole-5-carboxylate Hydrochloride (23)
The isoxazolone (17) (1.0 g, 1.9 mmol) was photolyzed through pyrex
at 300 nm in anhydrous ethyl acetate (1000 mL) under N2 at rt for
5 h. The solvent was evaporated and the residue was purified by
radial chromatography (10% ethyl acetate/light petroleum) to give two
fractions.
A mixture of (21) (160 mg, 0.509 mmol) and hydrazine hydrate (30 µL,
0.617 mmol) in ethanol (6 mL) yielded the title compound as a yellow
oil (77 mg, 69%) (Found: [M + H]+•, 185.0920. C8H12N2O3 requires
[M + H]+•, 185.0926). νmax/cm−1 3600–2400br, 1726, 1593, 1315,
1146. δH 9.10 (3 H, br s), 7.76 (1 H, s), 5.00 (1 H, br s), 4.37 (2 H,
q, J 6.9), 1.87 (3 H, br s), 1.37 (3 H, t, J 6.9). δC 163.5, 157.5, 143.4,
133.9, 61.7, 45.5, 17.3, 14.0.
The first fraction contained (S)-ethyl 2-[2-(4-benzyloxyphenyl)-
1-phthalimidoethyl]oxazole-5-carboxylate (24) (0.438 g, 48%), which
was isolated as a yellow oil, [α]D −101◦ (c 2.8 in CHCl3) (Found:
20
M+•, 496.1634. C29H24N2O6 requires M+•, 496.1635). νmax/cm−1
1717, 1458, 1381, 1244, 1145. δH 7.78 (2 H, m), 7.71 (1 H, s), 7.70
(2 H, m), 7.37–7.32 (5 H, m), 7.13 (2 H, d, J 8.8), 6.82 (2 H, d, J 8.8),
5.72 (1 H, dd, J 6.5 and 10.0), 4.96 (2 H, s), 4.36 (2 H, q, J 7.1), 3.73
(2 H, m), 1.36 (3 H, t, J 7.1). δC 167.1, 163.7, 157.8, 143.1, 136.8,
134.2, 134.0, 131.4, 130.0, 128.4, 128.1, 127.8, 127.4, 123.6, 115.0,
105.5, 69.9, 61.5, 49.4, 34.7, 14.2. m/z 496 (3%, M+•), 451 (2), 423
(6), 350 (32), 83 (100), 43 (74).
(S)-Ethyl 2-[1-Amino-2-(4-benzyloxyphenyl)ethyl]-
1,3-oxazole-5-carboxylate (25)
A solution containing the protected oxazole (24) (0.438 g, 0.88 mmol)
and hydrazine hydrate (176 µL, 3.96 mmol) in ethanol (20 mL)
was reacted as described above to give (25) (0.3 g, 93%) as an
20
orange oil, which required no further purification, [α]D –16.6◦ (c
0.84 in CHCl3) (Found: [M + H]+•, 367.1655. C21H22N2O4 requires
[M + H]+•, 367.1658). νmax/cm−1 3290, 1724 (ester C O), 1511, 1302,
1241, 1145. δH 7.66 (1 H, s), 7.43–7.31 (5 H, m), 7.05 (2 H, d, J 8.5),
6.88 (2 H, d, J 8.5), 5.02 (2 H, s), 4.38 (2 H, q, J 7.1), 4.32 (1 H, dd, J 5.5
and 8.0), 4.01 (2 H, br s), 3.21 (1 H, dd, J 5.5 and 13.6), 2.99 (1 H, dd,
J 8.0 and 13.6), 1.38 (3 H, t, J 7.14). δC 169.6, 157.7, 142.3, 136.9,
133.7, 130.2, 128.8, 128.6, 128.4, 127.8, 127.3, 114.9, 69.9, 61.4,
51.6, 41.1, 14.1. m/z 367 (5%, [M + H]+•), 322 (10), 294 (12),
276 (2), 260 (4), 91 (100).
The second fraction contained O-benzylphthalimidotyrosine
(0.265 g, 36%), which was isolated as a white solid. The spectral data
was identical to that above, mp 210–212◦C.
Ethyl 2-(Aminomethyl)-1,3-oxazole-5-carboxylate Hydrochloride (8)
A suspension of (18) (400 mg, 1.33 mmol) and hydrazine hydrate
(78 µL, 1.60 mmol) in ethanol (16 mL) was stirred for 2 h at 60◦C.