StereoselectiVe Formation of Fused Tricyclic Amines
salt (140 mg, 100%), which recrystallized from CH2Cl2-
Et2O-petroleum ether as cubes: mp 184-186 °C; νmax/cm-1 2965,
2930, 2365, 1720; 1H NMR (400 MHz, CDCl3) δ ) 13.10 (1H, br
s, NH), 7.95 (2H, d, J 8.5 Hz, ArH), 7.59 (2H, d, J 8.5 Hz, ArH),
4.99-4.90 (1H, m, CH), 4.84 (1H, br d, J 11.5 Hz, CH), 4.36 (1H,
br t, J 6.0 Hz, CH), 3.87 (2H, br s, 2 × CH), 3.26 (1H, br s, CH),
2.93-2.83 (1H, m, CH), 2.25-1.98 (4H, m, 4 × CH), 1.90-1.42
(6H, m, 6 × CH), 0.94 (3H, t, J 7.0 Hz, CH3); 13C NMR (75 MHz,
CDCl3) δ ) 164.3, 131.1, 130.5, 128.0, 126.8, 81.1, 64.0, 61.8,
54.3, 52.0, 41.3, 35.0, 33.2, 33.0, 29.5, 29.4, 8.9; HRMS (ES) found
MH+ 378.1059, C19H25NO279Br requires MH+ 378.1069; LRMS
m/z (ES) 380 (100, MH+ (81Br)), 378 (100, MH+ (79Br)); Anal.
Calcd for C19H26BrClNO2: C, 55.02; H, 6.08; N, 3.38; Br, 19.26;
Cl, 8.55. Found: C, 54.75; H, 6.02; N, 3.16; Br, 19.23; Cl, 8.54.
X-ray crystal structure analysis: Detailed results are deposited
at the Cambridge Crystallographic Data Centre. Structure No.
CCDC-694395.
) 87.0, 73.5, 66.8, 44.7, 36.0, 34.8, 30.3, 28.5, 27.7, 24.7, 21.4,
20.6, 7.0; HRMS (ES) found MH+ 210.1853, C13H24NO requires
MH+ 210.1858; LRMS m/z (ES) 210 (100, MH+).
2-Ethylhept-6-ynenitrile 42. n-Butyllithium (16.56 mL, 35.6
mmol, 2.5 M in hexanes) was added to diisopropylamine (5.26 mL,
37 mmol) in THF (40 mL) at -78 °C. After 10 min, butyronitrile
(6.2 mL, 71.2 mmol) was added dropwise. After 10 min, the
5-bromo-1-pentyne (2.4 g, 18 mmol) was added, and the mixture
was allowed to warm to room temperature. After 1 h, saturated
aqueous ammonium chloride solution (30 mL) was added, and the
mixture was extracted with Et2O (3 × 50 mL). The organic layers
were combined, dried (MgSO4), and evaporated. Purification by
column chromatography, eluting with petroleum ether-EtOAc (97:
3), gave the nitrile 42 (1.5 g, 64%) as an oil: Rf 0.50 [petroleum
ether-EtOAc (19:1)]; νmax/cm-1 3295, 2960, 2235, 1460; 1H NMR
(400 MHz, CDCl3) δ ) 2.52 (1H, quin, J 7.0 Hz, CH), 2.28 (2H,
td, J 6.5, 2.5 Hz, CH2), 1.99 (1H, t, J 2.5 Hz, CH), 1.85-1.60
(6H, m, 3 × CH2), 1.10 (3H, t, J 7.5 Hz CH3); 13C NMR (63 MHz,
CDCl3) δ ) 121.8, 84.1, 69.2, 32.9, 30.8, 25.8, 25.5, 18.0, 11.5;
HRMS (EI) found M+ 135.1048, C9H13N requires M+ 135.1054;
LRMS m/z (EI) 135 (10, M+), 107 (100).
(2aSR,4aSR,6bSR)-4a-Ethyloctahydro-1-oxa-6a-azacyclopen-
ta[cd]pentalene 34. The aldehyde 9 (385 mg, 2.04 mmol),
hydroxylamine hydrochloride (213 mg, 3.06 mmol), and N,N-
diisopropylethylamine (1.08 mL, 6.12 mmol) were heated under
reflux in toluene (20 mL). After 2 h, the solvent was evaporated,
and the residue was purified by column chromatography, eluting
with EtOAc, to give cycloadduct 34 (303 mg, 89%) as an oil: Rf
2-(3-Chloropropyl)-2-ethylhept-6-ynenitrile 43. In the same
way as the nitrile 42, n-butyllithium (13.3 mL, 33.3 mmol, 2.5 M
in hexanes), diisopropylamine (4.6 mL, 35.8 mmol), nitrile 42 (2.9
g, 21.5 mmol), and 1,3-bromochloropropane (3.29 mL, 33.3 mmol)
gave, after purification by column chromatography, eluting with
petroleum ether-EtOAc (97:3), the nitrile 43 (2.9 g, 63%) as an
oil: Rf 0.40 [petroleum ether-EtOAc (19:1)]; νmax/cm-1 3250, 2985,
1
0.20 (EtOAc); νmax/cm-1 2955, 2865, 2855; H NMR (400 MHz,
CDCl3) δ ) 3.66 (1H, dd, J 9.0, 6.0 Hz, CH), 3.55 (1H, dd, J 9.0,
2.5 Hz, CH), 3.48 (1H, d, J 9.0 Hz, CH), 3.26 (1H, ddd, J 13.0,
6.5, 3.5 Hz, CH), 3.02-2.86 (2H, m, 2 × CH), 1.89-1.80 (1H, m,
CH), 1.79-1.70 (1H, m, CH), 1.65-1.29 (6H, m, 6 × CH), 0.84
(3H, t, J 7.5 Hz, CH3); 13C NMR (75 MHz, CDCl3) δ ) 80.8,
70.2, 54.9, 54.7, 48.9, 35.6, 33.4, 30.0, 29.7, 9.1; HRMS (ES) found
MH+ 168.1388, C10H18NO requires MH+ 168.1388; LRMS m/z
(ES) 168 (100, MH+).
1
2235, 1460; H NMR (400 MHz, CDCl3) δ ) 3.60 (2H, t, J 6.5
Hz, CH2), 2.26 (2H, td, J 6.5, 2.5 Hz, CH2), 2.00 (1H, t, J 2.5 Hz,
CH) 1.95-1.87 (2H, m, 2 × CH), 1.75-1.60 (8H, m, 8 × CH),
1.03 (3H, t, J 7.5 Hz, CH3); 13C NMR (100 MHz, CDCl3) δ )
123.3, 83.2, 69.3, 44.6, 40.5, 34.5, 33.0, 28.9, 27.5, 23.2, 18.4, 8.6;
HRMS (EI) found M+ 211.1129, C12H18NCl requires M+ 211.1122;
LRMS m/z (EI) 211 (15, M+), 67 (100).
[(3aSR,6RS,6aSR)-3a-Ethyloctahydrocyclopenta[b]pyrrol-6-
yl]methanol 35. Zn powder (353 mg, 5.40 mmol) was added to
the hydroxylamine 34 (215 mg, 1.29 mmol) in AcOH/H2O (1:2, 8
mL), and the mixture was heated to 70 °C. After 30 min, the mixture
was cooled to room temperature, filtered, and washed with CH2Cl2.
The solvent was evaporated, and ammonia solution (10 mL) and
CH2Cl2 (20 mL) were added. The aqueous layer was extracted with
CH2Cl2 (3 × 30 mL), dried (MgSO4), and evaporated to give the
amino alcohol 35 (201 mg, 92%) as an oil: νmax/cm-1 3240, 2935,
2-(3-Chloropropyl)-2-ethylhept-6-ynal 44. In the same way as
the aldehyde 9, DIBAL-H (20 mL, 20 mmol, 1.0 M in hexanes)
and the nitrile 43 (2.8 g, 13.3 mmol) gave, after purification by
column chromatography, eluting with petroleum ether-EtOAc (97:
3), the aldehyde 44 (2.9 g, 64%) as an oil: Rf 0.3 [petroleum
ether-EtOAc (19:1)] νmax/cm-1 3300, 2945, 1710, 1460; 1H NMR
(400 MHz, CDCl3) δ ) 9.44 (1H, s, CHO), 3.54 (2H, m, CH2),
2.22 (2H, td, J 7.0, 2.5 Hz, CH2), 1.99 (1H, t, J 2.5 Hz, CH)
1.68-1.54 (2H, m, 2 × CH), 1.46-1.36 (8H, m, 8 × CH), 0.83
(3H, t, J 7.5 Hz, CH3); 13C NMR (63 MHz, CDCl3) δ ) 206.3,
83.7, 68.9, 51.7, 45.2, 30.5, 28.5, 26.7, 24.7, 22.5, 18.9, 7.8; HRMS
(EI) found M+ 214.1124, C12H19OCl requires M+ 214.1125; LRMS
m/z (EI) 215 (5, MH+), 55 (100).
1
2865, 1460, 1395, 1025; H NMR (500 MHz, CDCl3) δ ) 3.96
(1H, dd, J 11.5, 2.0 Hz, CH), 3.94 (1H, br s, NH), 3.70 (1H, dd, J
11.5, 4.0 Hz, CH), 3.30 (1H, d, J 6.0 Hz, CH), 2.91 (1H, dt, J
10.5, 6.5 Hz, CH), 2.83 (1H, dt, J 10.5, 6.5 Hz, CH), 1.92-1.80
(2H, m, 2 × CH), 1.61 (2H, td, J 6.5, 2.5 Hz, 2 × CH), 1.61-1.40
(5H, m, 5 × CH), 0.89 (3H, t, J 7.5 Hz, CH3); 13C NMR (125
MHz, CDCl3) δ ) 71.9, 63.0, 55.3, 47.4, 44.4, 39.2, 36.4, 33.3,
26.8, 10.1; HRMS (EI) found M+ 169.1466, C10H19NO requires
M+ 169.1467; LRMS m/z (ES) 170 (100, MH+).
(2SR,3aRS,6aSR)-Ethyl 6a-Ethyl-3,4,5,6,6a,7,8,9-octahydro-
2H-pyrrolo[3,2,1-ij]quinoline-2-carboxylate 45. In the same way
as the ester 24, the aldehyde 44 (0.26 g, (1.2 mmol), glycine ethyl
ester hydrochloride salt (0.26 g, 1.85 mmol), and N,N-diisopropy-
lethylamine (0.65 mL, 3.7mmol) gave, after purification by column
chromatography, eluting with petroleum ether-EtOAc (1:4), the
ester 45 (0.21 g, 65%) as an oil: Rf 0.30 [petroleum ether-EtOAc
(6aSR,9aRS,9bSR)-6a-Ethyloctahydro-2-oxa-3a-azaphe-
nalene 41. The amino alcohol 37 (233 mg, 1.18 mmol) and
TsOH·H2O (11 mg, 0.06 mmol) in CHCl3 (7.5 mL) were heated
under reflux. After 5 h, the mixture was allowed to cool to room
temperature, and H2O (6 mL) and potassium carbonate (1 g) were
added. The mixture was extracted with CH2Cl2 (2 × 15 mL), and
the organic layer was dried (MgSO4) and evaporated. Purification
by column chromatography, eluting with petroleum ether-EtOAc
(9:1), gave the oxazine 41 (245 mg, 100%) as an oil: Rf 0.22
1
(1:4)]; νmax/cm-1 2935, 2865, 1745, 1460; H NMR (500 MHz,
CDCl3) δ )5.40 (1H, q, J 2.5 Hz, CH), 4.21-4.06 (2H, m, CH2)
3.91 (1H, d, J 2.5 Hz, CH), 3.74 (1H, s, CH), 2.90 (1H, d, J 11.0
Hz, CH), 2.60 (1H, d, J 13.5 Hz, CH), 2.36 (1H, td, J 11.0, 3.5
Hz, CH), 2.04-1.88 (4H, m, 4 × CH), 1.80 (1H, qt, J 13.0, 3.5
Hz, CH), 1.63-1.53 (1H, m, CH), 1.52-1.36 (4H, m, 4 × CH),
1.26 (3H, t, J 7.0 Hz, CH3), 1.22-1.17 (1H, m, CH), 0.86 (3H, J
7.5 Hz, CH3); (125 MHz, CDCl3) δ ) 171.5, 143.9, 117.5, 73.3,
70.5, 60.6, 50.6, 35.3, 34.6, 32.7, 29.7, 26.7, 26.0, 20.0, 14.2, 7.6;
HRMS (ES) found M+ 263.1885, C16H25NO2 requires M+ 263.1890;
LRMS m/z (ES) 264 (100, MH+).
1
[petroleum ether-EtOAc (9:1)]; νmax/cm-1 2920, 2845, 1460; H
NMR (500 MHz, CDCl3) δ ) 4.44 (1H, dd, J 10.5, 0.5 Hz, CH),
4.40 (1H, d, J 10.5 Hz, CH), 3.86 (1H, ddd, J 12.0, 4.0, 0.5 (CH),
3.19 (1H, td, J 12.0, 3.5 Hz, CH), 3.15 (1H, t, J 11.0 Hz, CH),
2.61 (1H, br dd, J 11.0, 5.0 Hz, CH), 2.33 (1H, d, J 11.0 Hz, CH),
2.30-2.21 (1H, m, CH), 1.95-1.87 (1H, m, CH), 1.79-1.69 (1H,
m, CH), 1.59 (1H, td, J 13.5, 4.0 Hz, CH), 1.55-1.34 (5H, m, 5 ×
CH), 1.25-1.09 (3H, m, 3 × CH), 0.76 (3H, t, J 7.5 Hz, CH3),
0.72 (1H, dd, J 12.0, 3.5 Hz, CH); 13C NMR (125 MHz, CDCl3) δ
4a-Ethyl-1,2,3,4,4a,5,6,7-octahydroquinoline-8-carbalde-
hyde 46. Hydroxylamine hydrochloride (0.11 g, 1.52 mmol), N,N-
diisopropylethylamine (0.52 mL, 3.0 mmol), and the aldehyde 44
J. Org. Chem. Vol. 74, No. 6, 2009 2299