Cycloalkanecarboxylic Acids by Intramolecular Conjugate Addition
tion mixture was poured into cold saturated aq. NH4Cl and ex-
tracted with EtOAc. The extract was washed with brine, dried
(MgSO4), and concentrated in vacuo. The residue was purified by
flash column chromatography (hexane/EtOAc = 5:1) to give the
trichloroacetimidate 2b (1.052 g; 79% yield) as a colorless solid. An
analytical sample (colorless powder) was obtained by recrystalli-
around 30 min. A 1 NaOH solution (1.3 mL) and saturated aq.
NaHCO3 were successively added to the reaction mixture. The
whole mixture was extracted with EtOAc. The extract was washed
with brine, dried (MgSO4), and concentrated in vacuo. The residue
was purified by flash column chromatography (hexane/EtOAc =
1:1) to give compound 5b (67.2 mg, 98%) as a colorless solid. An
analytical sample (colorless powder) was obtained by recrystalli-
zation from hexane; m.p. 47.5–50.0 °C. IR (KBr): ν
= 3303,
˜
max
2954, 1711, 1668, 1439, 1288, 1242, 1076, 1028, 991, 796, 646 cm–1. zation from EtOAc/hexane; m.p. 74.5–76.0 °C. IR (KBr): ν
=
˜
max
1H NMR (270 MHz, CDCl3): δ = 8.34 (br. s, 1 H), 6.82 (ddd, J =
2.1, 2.1, 4.1 Hz, 1 H), 5.97–5.88 (m, 1 H), 3.78 (s, 3 H), 2.89–2.73
(m, 1 H), 2.67–2.44 (m, 2 H), 2.17–2.01 (m, 1 H) ppm. 13C NMR
3496, 3323, 2956, 1736, 1697, 1522, 1431, 1365, 1223, 1165, 1053,
1
835, 820, 640 cm–1. H NMR (270 MHz, CDCl3): δ = 7.36 (br. d,
J = 4.1 Hz, 1 H), 4.46–4.37 (m, 1 H), 4.28 (ddd, J = 4.6, 7.7, 9.5 Hz,
(67.8 MHz, CDCl3): δ = 165.1, 162.1, 141.7, 138.0, 91.4, 84.1, 51.8, 1 H), 3.71 (s, 3 H), 2.91 (ddd, J = 8.2, 9.2, 9.2 Hz, 1 H), 2.27–1.91
30.1, 29.6 ppm. C9H10Cl3NO3 (286.54): calcd. C 37.72, H 3.52, N
4.89; found C 37.53, H 3.45, N 4.83.
(m, 3 H), 2.00 (d, J = 3.6 Hz, 1 H), 1.88–1.73 (m, 1 H) ppm. 13C
NMR (67.8 MHz, CDCl3): δ = 174.5, 161.8, 92.5, 72.7, 58.9, 52.3,
46.9, 32.4, 24.7 ppm. C9H12Cl3NO4 (304.55): calcd. C 35.49, H
3.97, N 4.60; found C 35.42, H 3.92, N 4.59.
Methyl
(3aR*,4S*,6aS*)-2-Trichloromethyl-4,5,6,6a-tetrahydro-
3aH-cyclopenta[d]oxazole-4-carboxylate (3b) and Methyl (3aR*,4R*,
6aS*)-2-Trichloromethyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[d]-
oxazole-4-carboxylate (4b): DBU (59.0 µL, 0.395 mmol) was added
dropwise to a solution of the trichloroacetimidate 2b (101.7 mg,
0.355 mmol) in anhydrous CH2Cl2 (14.0 mL) at room temp. and
the mixture was stirred for around 24 h under a dry atmosphere
(calcium chloride tube). The reaction mixture was poured into satu-
rated aq. NH4Cl and extracted with EtOAc. The extract was
washed with brine, dried (MgSO4), and concentrated in vacuo. The
residue was purified by flash column chromatography (hexane/
EtOAc = 3:1) to give the oxazolines 3b (colorless solid, 83.4 mg,
82%, less polar) and 4b (colorless solid, 4.7 mg, 4.6%, more polar).
Analytical samples of 3b (colorless powder) and 4b (colorless need-
les) were obtained by recrystallization from EtOAc/hexane.
Methyl
(1R*,2R*,3S*)-2-Trichloroacetamido-3-hydroxycyclopen-
tanecarboxylate (6b): A 1 HCl (1.4 mL) was added dropwise to
an ice-cooled solution of the oxazoline 4b (62.4 mg, 0.218 mmol)
in THF (5.0 mL) and the mixture was stirred for around 30 min.
A 1 NaOH solution (1.3 mL) and saturated aq. NaHCO3 were
successively added to the reaction mixture. The whole mixture was
extracted with EtOAc. The extract was washed with brine, dried
(MgSO4), and concentrated in vacuo. The residue was purified by
flash column chromatography (hexane/EtOAc = 1:1) to give com-
pound 6b (54.8 mg, 83%) as a colorless solid. An analytical sample
(colorless powder) was obtained by triturating in cold EtOAc/hex-
ane; m.p. 36.0–36.5 °C. IR (KBr): ν
= 3365, 3236, 2951, 1711,
˜
max
1520, 1441, 1375, 1227, 1209, 1173, 1003, 843, 823 cm–1. H NMR
(270 MHz, CDCl3): δ = 7.70 (br. s, 1 H), 4.30–4.14 (m, 2 H), 3.71
(s, 3 H), 3.48–3.38 (m, 1 H), 3.23 (d, J = 9.8 Hz, 1 H), 2.30–1.92
(m, 4 H) ppm. 13C NMR (67.8 MHz, CDCl3): δ = 176.9, 161.9,
92.3, 72.8, 56.7, 52.6, 44.7, 32.7, 26.0 ppm. C9H12Cl3NO4 (304.55):
calcd. C 35.49, H 3.97, N 4.60; found C 35.48, H 3.93, N 4.53.
1
Oxazoline 3b: Colorless powder; m.p. 51.5–52.5 °C. IR (KBr): ν
˜
max
= 2976, 2951, 1728, 1653, 1433, 1362, 1329, 1238, 1207, 1196, 1176,
1
1167, 999, 872, 812, 800, 681 cm–1. H NMR (270 MHz, CDCl3):
δ = 5.39 (ddd, J = 1.7, 5.3, 7.5 Hz, 1 H), 5.04 (dd, J = 1.3, 7.5 Hz,
1 H), 3.71 (s, 3 H), 3.16–3.09 (m, 1 H), 2.19–1.79 (m, 4 H) ppm.
13C NMR (67.8 MHz, CDCl3): δ = 173.8, 163.2, 89.0, 86.3, 74.5,
52.2, 50.3, 32.7, 26.6 ppm. C9H10Cl3NO3 (286.54): calcd. C 37.72,
H 3.52, N 4.89; found C 37.69, H 3.52, N 4.85.
(1S*,2R*,3S*)-2-Amino-3-hydroxycyclopentanecarboxylic
Acid
(8b): A 3 HCl solution (8.0 mL) was added to the oxazoline 3b
(86.4 mg, 0.302 mmol) and the mixture was heated at 75 °C for
around 7 h. The whole mixture was concentrated in vacuo. The
obtained crude oily hydrochloride [1H NMR (270 MHz, D2O, ref-
erenced to the residual signal of HOD at δ = 4.65 ppm): δ = 4.23
(ddd, J = 2.5, 4.8, 4.8 Hz, 1 H), 3.64 (dd, J = 4.7, 9.4 Hz, 1 H),
2.95 (ddd, J = 8.1, 9.8, 9.8 Hz, 1 H), 2.24–2.06 (m, 1 H), 2.00–1.85
(m, 1 H), 1.82–1.59 (m, 2 H) ppm] was treated with 1 NH3 and
concentrated in vacuo. The residual free amino acid was purified by
recrystallization from H2O/acetone to give compound 8b (31.7 mg,
Oxazoline 4b: Colorless needles; m.p. 128.0–128.5 °C. IR (KBr):
ν
= 2983, 2947, 1734, 1653, 1437, 1250, 1201, 995, 945, 850,
˜
max
783, 658 cm–1. 1H NMR (270 MHz, CDCl3): δ = 5.35 (ddd, J =
1.5, 5.6, 7.2 Hz, 1 H), 5.00 (dd, J = 7.6, 7.6 Hz, 1 H), 3.75 (s, 3 H),
3.00 (ddd, J = 7.9, 7.9, 10.3 Hz, 1 H), 2.30–2.20 (m, 1 H), 2.00–
1.70 (m, 3 H) ppm. 13C NMR (67.8 MHz, CDCl3): δ = 170.9,
163.5, 88.4, 86.2, 73.3, 52.0, 50.1, 33.1, 24.3 ppm. C9H10Cl3NO3
(286.54): calcd. C 37.72, H 3.52, N 4.89; found C 37.62, H 3.45, N
4.86.
72%) as colorless needles; m.p. 231–235 °C (dec.). IR (KBr): ν
˜
max
= 3103, 2954, 2696, 2617, 2557, 1630, 1577, 1533, 1406, 1338, 1279,
1049, 970, 781, 717, 584, 453 cm–1. 1H NMR (270 MHz, D2O,
30 °C, referenced to the residual signal of HOD at δ = 4.65 ppm):
δ = 4.28 (ddd, J = 2.7, 5.2, 5.2 Hz, 1 H), 3.57 (dd, J = 5.0, 9.5 Hz,
1 H), 2.76 (ddd, J = 9.2, 9.2, 9.2 Hz, 1 H), 2.25–1.93 (m, 2 H), 1.76–
1.57 (m, 2 H) ppm. 13C NMR (67.8 MHz, D2O, 30 °C, acetone as
internal reference at δ = 30.6 ppm): δ = 181.3, 71.3, 57.6, 48.2, 31.4,
One-Pot Procedure: DBU (18.6 µL, 0.124 mmol) was added drop-
wise to an ice-cooled solution of the allylic alcohol 1b (58.3 mg,
0.410 mmol) and trichloroacetonitrile (62.0 µL, 0.618 mmol) in an-
hydrous CH2Cl2 (2.7 mL) and the mixture was stirred for around
17 h under a dry atmosphere (calcium chloride tube). An ad-
ditional amount of DBU (49.0 µL, 0.328 mmol) was added to the
reaction mixture, which was stirred for around 9 h. The reaction
mixture was poured into cold saturated aq. NH4Cl and extracted
with EtOAc. The extract was washed with brine, dried (MgSO4),
and concentrated in vacuo. The residue was purified by flash col-
umn chromatography to give the oxazolines 3b (102.8 mg, 87%)
and 4b (5.7 mg, 4.9%) in the same way as described above.
25.8 ppm. HRMS (ESI-TOF): calcd. for C6H12NO3 [M
+
H]+ 146.08172; found 146.0781.
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of H and 13C NMR spectra.
Methyl
(1S*,2R*,3S*)-2-Trichloroacetamido-3-hydroxycyclopen-
Acknowledgments
tanecarboxylate (5b): A 1 HCl solution (1.4 mL) was added drop-
wise to an ice-cooled solution of the oxazoline 3b (64.4 mg,
0.225 mmol) in THF (5.0 mL) and the mixture was stirred for
This work was supported by the Ministry of Education, Culture,
Sports, Science and Technology of Japan (17780089, Grant-in-Aid
Eur. J. Org. Chem. 2009, 1619–1624
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1623