3188
M. Periasamy et al.
PAPER
lated. The configuration at the newly formed chiral centers was
Anal. Calcd for C12H19NO2: C, 68.87; H, 9.15; N, 6.69; O, 15.29.
Found: C, 68.81; H, 9.23; N, 6.73; O, 15.32.
assigned as S,R by comparison with reported data.9
Yield: 1.62 g (95%); white solid; mp 255–257 °C (Lit.9 256–
(1R,2S,3R,4S)-(+)-3-(2-Hydroxyethylamino)-1,7,7-trimethylbi-
cyclo[2.2.1]heptan-2-ol (9)
25
20
258 °C); [α]D –17.3 (c 0.52, EtOH) {Lit.11 [α]D –17.5 (c 6.0,
EtOH)}.
To a stirred solution of 1 (1.66 g, 10 mmol) and ethanol amine 7
(1.11 mL, 10 mmol) in anhydrous toluene (15 mL), PTSA (0.01 g,
5 mol%) was added carefully. The reaction mixture was heated at
reflux for 6 h using a Dean–Stark apparatus. The mixture was
brought to 25 °C and the toluene layer was taken and dried
(Na2SO4) and the solvent was evaporated. The imine residue was
taken in MeOH (50 mL) and the contents were cooled to 0 °C.
NaBH4 (0.95 g, 25 mmol) was added in portions over a period of 1
h and the mixture was stirred further for 4 h at 0–25 °C. The MeOH
was removed under reduced pressure and H2O (10 mL) and EtOAc
(25 mL) were added. The organic layer was separated and washed
with sat. NaCl (2 × 10 mL), dried (Na2SO4), and the solvent was
evaporated. After column chromatography on silica gel (100–200;
EtOAc), product 9 was isolated. The configuration at the newly
formed chiral centers was assigned as S,R by comparison with re-
ported data for compound 5.6
Yield: 1.82 g (85%); white solid; mp 45–50 °C; [α]D25 +6.1 (c 0.60,
CHCl3).
IR (KBr): 3414, 2953, 2876, 1575, 1456, 1385, 1095 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.66–3.63 (m, 2 H), 3.43–3.41 (d,
J = 8.0 Hz, 1 H), 2.90–2.87 (m, 1 H), 2.70–2.65 (m, 2 H), 1.68–
1.62 (m, 2 H), 1.44–1.42 (m, 1 H), 1.03–1.01 (m, 5 H), 0.98 (s,
3 H), 0.97 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 78.9, 66.3, 61.6, 52.6, 51.6, 48.2,
46.5, 32.9, 27.1, 21.9, 21.2, 11.3.
IR (KBr): 3331, 2955, 1481, 1460, 1392, 1130, 1091, 1053 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.82–3.81 (d, J = 4.0 Hz, 1 H),
3.59–3.58 (d, J = 4.0 Hz, 1 H), 3.10 (s, 1 H), 2.99 (s, 1 H), 1.76–
1.75 (d, J = 4.0 Hz, 1 H), 1.65–1.63 (m, 1 H), 1.47–1.42 (m, 1 H),
1.09 (s, 3 H), 0.98–0.93 (m, 5 H), 0.79 (s, 3 H).
13C (100 MHz, CDCl3): δ = 79.8, 76.0, 51.4, 48.7, 46.4, 33.1, 24.0,
21.8, 21.0, 11.1.
MS (EI): m/z = 170 [M + 1].
(1R,2S,3R,4S)-(–)-3–Amino-1,7,7-trimethylbicyclo[2.2.1]hep-
tan-2-ol (5)
To a stirred solution of 1 (1.66 g, 10 mmol) in MeOH (5 mL), a so-
lution of NH3 (3; 1 M in MeOH; 15 mL) was added carefully and
the reaction mixture was stirred for 12 h at 25 °C. MeOH (30 mL)
was added and the mixture was cooled to 0 °C. NaBH4 (0.95 g, 25
mmol) was added in portions over a period of 1 h and the mixture
was stirred further for 2 h at 0–25 °C. MeOH was removed under
reduced pressure and H2O (10 mL) and CH2Cl2 (20 mL) were add-
ed. The organic layer was separated, washed with sat. NaCl (2 × 10
mL) and dried (Na2SO4). After evaporation of CH2Cl2, the crude
product was washed with hexane (2 × 5 mL) and the product 56 was
isolated. The configuration at the newly formed chiral centers were
assigned as S,R by comparison with reported data.6b
Yield: 1.40 g (83%); white solid; mp 210–215 °C (Lit.6b 211–
25
20
212 °C); [α]D –8.1 (c 0.52, CH3OH) {Lit.6b [α]D –8.2 (c 1.15,
MS (EI): m/z = 215.
CH3OH)}.
Anal. Calcd for C12H23NO2: C, 67.57; H, 10.87; N, 6.57; O, 15.00.
Found: C, 67.54; H, 10.82; N, 6.65; O, 14.95.
IR (KBr): 3414, 2953, 2876, 1575, 1456, 1385, 1095 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.38–3.36 (d, J = 4.0 Hz, 1 H),
3.06–3.04 (d, J = 8.0 Hz, 1 H), 1.70–1.69 (m, 2 H), 1.56–1.55 (d,
J = 4.0 Hz, 1 H), 1.45–1.43 (s, 1 H), 1.03 (s, 3 H), 0.90 (s, 3 H),
0.79 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 79.0, 57.3, 53.4, 48.7, 46.6, 33.1,
26.9, 21.9, 21.2, 11.4.
(1R,2S,3R,4S)-(–)-1,7,7-Trimethyl-3-(1,7,7-trimethylbicyclo-
[2.2.1]hept-2-ylamino)bicyclo[2.2.1]hept-2-ol (12)
To a stirred solution of 1 (0.836 g, 5 mmol), and exo-(–)-bornyl-
amine 10 (0.77 g, 5 mmol) in anhydrous toluene (15 mL), PTSA
(0.01 g, 5 mol%) was added carefully and the reaction mixture was
heated at reflux for 6 h using a Dean–Stark apparatus. The contents
were brought to 25 °C and the toluene layer was separated, dried
(Na2SO4), and the solvent was removed. The imine residue 11 was
taken in MeOH (25 mL) and cooled to 0 °C. NaBH4 (0.57 g, 15
mmol) was added in portions over a period of 1 h and stirred further
for 3 h at 0–25 °C. MeOH was removed under reduced pressure and
H2O (10 mL) and EtOAc (20 mL) were added. The organic layer
was separated, washed with sat. NaCl (2 × 5 mL), dried (Na2SO4),
and the solvent was evaporated. After column chromatography on
silica gel (100–200; hexane–EtOAc, 9:1), 12 was isolated. The con-
figuration at the newly formed chiral centers was assigned as S,R by
considering endo,endo attack on the ketimine 11 by NaBH4.6
MS (EI): m/z = 170.
(1R,2S,7R,8S)-(+)-1,11,11-Trimethyl-3-oxa-6-aza-tricyclo-
[6.2.1.02,7]undecan-5-one (6)
To a stirred solution of amino alcohol 5 (0.154 g, 1 mmol) and Et3N
(0.21 mL, 1 mmol) in anhydrous THF (5 mL), was added carefully
chloroacetyl chloride (0.12 g, 1.1 mmol). The contents were stirred
for 6 h and brought to 0 °C. Aq NaOH (1 M, 3 mL) was added and
the mixture was stirred for 2 h at 25 °C. CH2Cl2 (10 mL) was added
and the organic layer was separated, washed with sat. NaCl (2 × 5
mL), dried (Na2SO4), and the solvent was evaporated. After column
chromatography on silica gel (100–200; hexane–EtOAc), product 6
was isolated.5d
25
Yield: 1.14 g (75%); white solid; mp 115–120 °C; [α]D –60.1 (c
0.53, CHCl3).
25
Yield: 0.12 g (60%); white solid; mp 45–50 °C; [α]D +95.1 (c
IR (KBr): 3356, 3260, 2951, 2876, 1479, 1450, 1386, 1369, 1114,
1057, 960 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.33–3.32 (d, J = 4.0 Hz, 1 H),
2.68–2.66 (t, J = 12.0 Hz, 2 H), 1.70–1.40 (m, 9 H), 1.06–1.04 (m,
3 H), 0.99 (s, 3 H), 0.95 (s, 3 H), 0.92 (s, 3 H), 0.88 (s, 3 H), 0.80 (s,
3 H), 0.77 (s, 3 H).
0.60, CHCl3).
IR (KBr): 3414, 2953, 2876, 1675, 1456, 1385, 1095 cm–1.
1H NMR (400 MHz, CDCl3): δ = 6.93 (s, 1 H), 4.11–4.07 (d,
J = 16.0 Hz, 1 H), 3.77–3.74 (d, J = 12.0 Hz, 1 H), 3.64–3.63 (d,
J = 4.0 Hz, 1 H), 3.35–3.33 (d, J = 8.0 Hz, 1 H), 1.74–1.70 (m,
2 H), 1.58–1.55 (m, 1 H), 1.10 (s, 3 H), 1.06–1.03 (m, 2 H), 0.97 (s,
3 H), 0.83 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 170.8, 83.7, 66.2, 58.4, 50.5, 49.1,
47.5, 32.9, 25.9, 22.0, 20.5, 11.1.
13C NMR (100 MHz, CDCl3): δ = 78.8, 67.7, 65.5, 51.3, 48.7, 48.4,
46.6, 44.9, 38.5, 36.9, 33.0, 27.2, 21.9, 21.2, 20.6, 20.5, 12.1, 11.2.
MS (EI): m/z = 305.
Anal. Calcd for C20H35NO: C, 78.63; H, 11.55; N, 4.58; O, 5.24.
Found: C, 78.60; H, 11.63; N, 4.52; O, 5.33.
MS (EI): m/z = 210 [M + 1].
Synthesis 2012, 44, 3185–3190
© Georg Thieme Verlag Stuttgart · New York