S. Doherty, J. G. Knight, A. McRae, R. W. Harrington, W. Clegg
FULL PAPER
amine (3b; 0.32 g, 1.47 mmol). Yield: 0.58 g, 95%; white solid; m.p.
53.6, 47.5, 34.1, 31.8, 26.3, 26.1 ppm. IR: ν = 3390, 2960, 2885,
˜
58–60 °C. Rf = 0.30 (petroleum ether/ethyl acetate, 5:1). [α]D
=
1673, 1641, 1579, 1513, 1506, 1446, 1289 cm–1. MS (EI+): m/z (%)
= 315 (2.8) [M]+, 245 (100) [M – C4H8N]+, 218 (40), 161 (71), 146
(69), 70 (77) [C4H8N]+. HRMS (EI+): calcd. for C18H25N3O2
[M]+ 315.1947; found 315.1949. C18H25N3O2 (315.41): calcd. C
1
+89.5 (c = 0.20, CHCl3). H NMR (300 MHz, CDCl3, major rot-
amer): δ = 12.13 (br. s, 1 H, OCNH), 8.68 (d, J = 8.3 Hz, 1 H,
ArH), 7.76 (m, J = 7.9 Hz, 1 H, ArH), 7.40 (m, J = 8.3 Hz, 1 H,
ArH), 7.02 (m, J = 7.2 Hz, 1 H, ArH), 4.23–4.08 (m, 4 H, 68.54, H 7.99, N 13.32; found C 68.34, H 8.10, N 13.22.
CHNBoc, CH2O, CHN), 3.67–3.54 (m, 1 H), 3.51–3.42 (m, 1 H),
(2S)-N-{2-[(3aS,8aR)-8,8a-Dihydro-3aH-indeno(1,2-d)oxazol-2-yl]-
2.31–2.22 (m, 1 H), 2.12–2.00 (m, 1 H), 1.97–1.69 (m, 2 H), 1.23
phenyl}pyrrolidine-2-carboxamide (1c): This compound was pre-
[s, 9 H, C(CH3)3 (Boc)], 0.88 [s, 9 H, C(CH3)3] ppm. 13C NMR
pared from Boc-N-proline-oxazoline 4c (0.79 g, 1.77 mmol). Yield:
(75.5 MHz, CDCl3, major rotamer): δ = 172.5, 163.8, 154.6, 140.1,
0.46 g, 75%; white solid; m.p. 203–205 °C. Rf = 0.47 (CH2Cl2/meth-
132.6, 129.4, 122.5, 120.3, 114.1, 80.1, 76.5, 67.9, 62.9, 47.3, 34.4,
31.5, 28.6, 26.4, 24.9 ppm. In addition to these signals, the follow-
ing resonances were assigned to the minor rotamer (major/minor
anol, 9:1). [α]D = –7.9 (c = 0.22, CHCl3). 1H NMR (300 MHz,
[D4]MeOH): δ = 12.96 (br. s, 1 H, OCNH), 8.57 (dd, J = 1.1,
8.3 Hz, 1 H, ArH), 7.89 (dd, J = 1.5, 7.9 Hz, 1 H, ArH), 7.53 (m,
rotamer, 3:1): 1H NMR (300 MHz, CDCl3, minor rotamer): δ =
1 H, ArH indanol), 7.46 (m, J = 1.5, 8.3 Hz, 1 H, ArH), 7.29 (m,
1.35 [s, 9 H, C(CH3)3 (Boc)] ppm. 13C NMR (75.5 MHz, CDCl3,
3 H, ArH indanol), 7.15 (m, J = 1.1, 7.9 Hz, 1 H, ArH), 5.86 (d,
minor rotamer): δ = 172.1, 155.4, 80.5, 47.8, 28.8, 24.3 ppm. IR: ν
˜
J = 7.9 Hz, 1 H), 5.53 (m, J = 1.9, 6.8, 7.9 Hz, 1 H), 4.30 (m, 1
H), 3.57 (dd, J = 6.8, 18.1 Hz, 1 H), 3.37 (m, 1 H), 3.32 (m, 2 H),
2.44 (m, 1 H), 2.00 (m, 3 H) ppm. 13C NMR (75.5 MHz,
[D4]MeOH): δ = 172.2, 165.3, 143.3, 141.6, 140.2, 133.8, 130.9,
130.3, 128.8, 127.0, 126.7, 124.9, 121.6, 114.0, 84.3, 78.4, 63.4, 55.0,
= 2985, 2931, 1696, 1636, 1586, 1526, 1448, 1390, 1365 cm–1. MS
(EI+): m/z (%) = 416 (0.1) [M + H]+, 342 (9) [M – tBuO]+, 245
(100) [M – BocNC4H7]+, 146 (30), 114 (38), 70 (49), 57 (39)
[tBu]+. HRMS (EI+): calcd. for C23H34N3O4 [M + H]+ 416.2549;
found 416.2555.
40.9, 31.8, 26.2 ppm. IR: ν = 3365, 2971, 1681, 1627, 1588, 1538,
˜
General Procedure for the Synthesis of Proline-Oxazolines (1a–c):
To a solution of Boc-proline-oxazoline (1.0 equiv.) in CH2Cl2
(5.0 mL/mmol Boc-N-proline-oxazoline) was added trifluoroacetic
acid (20 equiv.), and the reaction was stirred at r.t. for 3 h. The
solvent was removed in vacuo, and the resulting residue was neu-
tralised with saturated aqueous NaHCO3 and extracted with
CH2Cl2 (3ϫ2 mL). The organic layer was separated and dried with
anhydrous MgSO4 and then filtered and concentrated under re-
duced pressure. Purification of the crude product by column
chromatography on silica gel (CH2Cl2/methanol, 9:1) gave the pure
title compounds.
1520, 1505, 1447, 1353, 1289 cm–1. MS (EI+): m/z (%) = 347 (0.6)
[M]+, 277 (100) [M – C4H8N]+, 250 (34), 146 (28), 115 (30), 70 (21)
[C4H8N]+. HRMS (EI+): calcd. for C21H21N3O2 [M]+ 347.1630;
found 347.1634.
(2R)-N-{2-[(S)-4-tert-Butyl-4,5-dihydrooxazol-2-yl]phenyl}pyrrol-
idine-2-carboxamide (1bЈ): This compound was prepared from Boc-
N-proline-oxazoline 4bЈ (0.58 g, 1.40 mmol). Yield: 0.23 g, 52%;
white solid; m.p. 100–102 °C. Rf = 0.50 (CH2Cl2/methanol, 9:1).
1
[α]D = +67.1 (c = 0.40, CHCl3). H NMR (300 MHz, CDCl3): δ =
12.53 (br. s, 1 H, OCNH), 8.69 (dd, J = 1.1, 8.7 Hz, 1 H, ArH),
7.77 (dd, J = 1.5, 7.9 Hz, 1 H, ArH), 7.38 (m, J = 1.5, 8.7 Hz, 1
(2S)-N-{2-[(S)-4,5-Dihydro-4-isopropyloxazol-2-yl]phenyl}pyrrol- H, ArH), 7.02 (m, J = 1.1, 7.9 Hz, 1 H, ArH), 4.25 (m, J = 11.7,
idine-2-carboxamide (1a): This compound was prepared from Boc-
N-proline-oxazoline 4a (0.95 g; 2.37 mmol). Yield: 0.55 g, 77 %;
white solid; m.p. 94–96 °C. Rf = 0.46 (CH2Cl2/methanol, 9:1). [α]D
= –67.6 (c = 0.88, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 12.59
13.2 Hz, 1 H, CHNH), 4.09 (m, 2 H, CH2O), 3.91 (dd, J = 6.0,
8.7 Hz, 1 H, CHN), 3.39 (br. s, 1 H, CH2NH), 3.04 (m, 2 H), 2.23
(m, 1 H), 1.99 (m, 1 H), 1.75 (m, 2 H), 0.91 [s, 9 H, C(CH3)3] ppm.
13C NMR (75.5 MHz, CDCl3): δ = 173.4, 163.7, 140.0, 132.6,
(br. s, 1 H, OCNH), 8.71 (dd, J = 1.1, 8.3 Hz, 1 H, ArH), 7.77 (dd, 129.6, 122.8, 120.5, 114.4, 67.8, 62.5, 47.4, 34.3, 34.2, 31.4, 26.3,
J = 1.5, 7.9 Hz, 1 H, ArH), 7.38 (m, J = 1.5, 8.3 Hz, 1 H, ArH),
25.9 ppm. IR: ν = 3360, 2966, 2867, 1690, 1634, 1622, 1588, 1532,
˜
7.00 (m, J = 1.1, 7.9 Hz, 1 H, ArH), 4.31 (dd, J = 7.9, 9.4 Hz, 1 1450, 1287 cm–1. MS (EI+): m/z (%) = 245 (100) [M – C4H8N]+,
H, CHNH), 4.09 (m, 1 H, CH2O), 3.98 (m, 1 H, CH2O), 3.83 (dd, 218 (6), 161 (16), 146 (19), 70 (21) [C4H8N]+. HRMS (EI+): calcd.
J = 5.7, 8.7 Hz, 1 H, CHN), 2.95 (m, 2 H), 2.16 (m, 3 H), 1.93 (m,
1 H), 1.73 [m, 1 H, CH(CH3)2], 1.00 [d, J = 6.8 Hz, 3 H,
for C14H17N2O2 [M
C18H25N3O2 (315.41): calcd. C 68.54, H 7.99, N 13.32; found C
–
C4H8N]+ 245.1290; found 245.1291.
CH(CH3)2], 0.91 [d, J = 6.8 Hz, 3 H, CH(CH3)2] ppm. 13C NMR 68.02, H 8.35, N 13.08.
(75.5 MHz, CDCl3): δ = 174.6, 163.4, 140.0, 132.5, 129.6, 122.7,
(S)-tert-Butyl-2-(phenylcarbamoyl)pyrrolidine-1-carboxylate (8):[15]
120.5, 114.5, 73.5, 69.5, 62.6, 47.6, 33.4, 31.7, 26.2, 19.0, 18.9 ppm.
N-methylmorpholine (0.91 mL, 8.25 mmol) and isobutylchlorofor-
mate (1.08 mL, 8.25 mmol) were added slowly to a solution of Boc-
-proline (1.62 g, 7.50 mmol) in THF (10 mL) at –15 °C and stirred
for 3 h. After this time, aniline (0.70 g, 7.50 mmol) was added, and
the reaction mixture was stirred overnight at r.t. The reaction mix-
IR: ν = 3390, 3050, 2960, 2870, 1672, 1640, 1579, 1513, 1447,
˜
1287 cm–1. MS (EI+): m/z (%) = 301 (2.5) [M]+, 231 (100) [M –
C4H8N]+, 204 (49), 161 (61), 146 (66), 70 (71) [C4H8N]+. HRMS
(EI+): calcd. for C17H23N3O2 [M]+ 301.1790; found 301.1797.
(2S)-N-{2-[(S)-4-tert-Butyl-4,5-dihydrooxazol-2-yl]phenyl}pyrrol- ture was then filtered through silica with ethyl acetate (200 mL),
idine-2-carboxamide (1b): This compound was prepared from Boc-
N-proline-oxazoline 4b (1.12 g, 2.70 mmol). Yield: 0.58 g, 68 %;
white solid; m.p. 110–112 °C. Rf = 0.47 (CH2Cl2/methanol, 9:1).
[α]D = –10.7 (c = 0.20, CHCl3). H NMR (300 MHz, CDCl3): δ =
12.77 (br. s, 1 H, OCNH), 8.76 (dd, J = 1.1, 8.3 Hz, 1 H, ArH),
and the solvent was removed under reduced pressure to leave a
white powder. The crude product was purified by recrystallisation
from CH2Cl2/pentane to yield the title product as colourless crys-
tals. Yield: 1.32 g, 61%; m.p. 185–188 °C. [α]D = –138.3 (c = 0.24,
CHCl3). 1H NMR (300 MHz, CDCl3): δ = 9.50 (br. s, 1 H,
1
7.88 (dd, J = 1.5, 7.9 Hz, 1 H, ArH), 7.47 (m, J = 1.5, 8.3 Hz, 1 OCNH), 7.52 (d, J = 7.6 Hz, 2 H, ArH), 7.28 (m, J = 7.2, 7.6 Hz,
H, ArH), 7.11 (m, J = 1.1, 7.9 Hz, 1 H, ArH), 4.33 (m, 1 H, 2 H, ArH), 7.10 (m, 1 H, ArH), 4.48 (m, 1 H, CHNBoc), 3.48 (m,
CHNH), 4.18 (m, 3 H, CH2O, CHN), 3.90–3.70 (br. s, 1 H,
2 H, CH2NBoc), 2.54 (m, 1 H), 1.96 (m, 3 H), 1.51 [s, 9 H,
CH2NH), 3.22 (m, 2 H), 2.33 (m, 1 H), 2.10 (m, 1 H), 1.89 (m, 2 C(CH3)3] ppm. 13C NMR (75.5 MHz, CDCl3): δ = 170.4, 156.4,
H), 0.99 [s, 9 H, C(CH3)3] ppm. 13C NMR (75.5 MHz, CDCl3): δ
= 174.0, 163.5, 140.0, 132.6, 129.5, 122.5, 120.5, 114.4, 67.7, 62.5,
138.6, 129.2, 124.4, 120.2, 81.2, 61.5, 47.6, 29.0, 28.8, 24.8 ppm.
IR: ν = 3271, 2967, 2876, 1667, 1548, 1398, 1154 cm–1. MS (EI+):
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Eur. J. Org. Chem. 2008, 1759–1766