1160
T. Yoshizumi et al.
PAPER
1H NMR (400 MHz, CDCl3): d = –0.24 (s, 3 H), 0.08 (s, 3 H), 0.85
(s, 9 H), 1.13 (tdd, J = 13.0, 12.5, 1.4 Hz, 1 H), 1.43 (ddd, J = 14.0,
12.5, 1.4 Hz, 2 H), 2.09–2.17 (m, 2 H), 2.44–2.54 (m, 1 H), 2.58
(ddd, J = 14.0, 7.0, 1.3 Hz, 1 H), 3.39 (t, J = 12.5 Hz, 1 H), 3.42–
3.57 (m, 2 H), 5.10 (d, J = 6.8 Hz, 1 H), 7.07 (dd, J = 7.3, 4.9 Hz, 1
H), 7.39 (dd, J = 7.3, 1.5 Hz, 1 H), 8.28 (dd, J = 4.9, 1.5 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = –5.3, –5.0, 18.1, 25.8, 31.1, 32.2,
35.9, 38.5, 68.9, 77.5, 122.4, 137.5, 138.1, 145.4, 162.0.
HRMS (ESI): m/z [M + H]+ calcd for C17H30NO2Si: 308.2046;
found: 308.2044.
Ethylcis-8-Hydroxy-5,6,7,8-tetrahydroquinoline-6-carboxylate
(35) and Ethyl trans-8-Hydroxy-5,6,7,8-tetrahydroquinoline-6-
carboxylate (36)
To a stirred soln of the crude 32 in CHCl3 (4.5 L) was added
MCPBA (869 g, ca. 65% purity) at 0 °C. The mixture was stirred at
r.t. for 2.5 h, MCPBA (174 g) was added again, and the mixture was
stirred for an additional 30 min. The reaction was quenched by the
addition of sat. aq NaHCO3, and the mixture was extracted with
CHCl3 (1 L). The combined organic layers were washed with sat. aq
NaHCO3, 10% aq Na2SO3, and brine, dried (Na2SO4), and concen-
trated by rotary evaporation to give crude N-oxide 33. The residue
was dissolved in Ac2O (2.0 L), and the resulting mixture was stirred
at 130 °C for 1 h. Ac2O was removed by rotary evaporation, and the
residue was partitioned with sat. aq NaHCO3 and CHCl3 (1 L). The
aqueous layer was extracted with CHCl3 (1 L), and the combined or-
ganic layers were washed with sat. aq NaHCO3 and brine, dried
(MgSO4), and concentrated by rotary evaporation to afford crude 34
as a mixture of cis- and trans-isomers. To a soln of crude 34 in THF
(3.0 L) cooled at 0 °C was added an EtOH soln of NaOEt [prepared
from Na (77.2 g, 3.36 mol) and EtOH (3.4 L)]. The mixture was
stirred at 0 °C for 30 min, and the reaction was quenched by the ad-
dition of sat. aq NH4Cl. The soln was concentrated by rotary evap-
oration, and the resulting mixture was partitioned with H2O and
CHCl3 (1.5 L). The organic layer was separated, and the aqueous
layer was extracted with CHCl3 (2 × 1.5 L). The combined organic
layers were washed with brine, dried (Na2SO4), and concentrated by
rotary evaporation. The residue was purified by column chromatog-
raphy (silica gel, n-hexane–EtOAc, 2:1 to 0:10) to give cis-isomer
35 (91.1 g, 14%) from a less polar fraction and trans-isomer 36 (336
g) from a polar fraction including some impurities, which was used
in the next step without further purification.
[(7R,9S)-9-(tert-Butyldimethylsiloxy)-7-[(tosyloxy)methyl]-
6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine [(–)-3]
To a stirred soln of 28 (6.90 g, 22.4 mmol) in CHCl3 (150 mL) were
added Et3N (9.40 mL, 67.4 mmol), DMAP (270 mg, 2.21 mmol),
and TsCl (8.54 g, 44.8 mmol) at r.t. The mixture was stirred at 50
°C for 2.5 h and then cooled to r.t. and diluted with Et2O (600 mL)
and H2O. The organic layer was separated, washed with sat. aq
NaHCO3 and brine, dried (Na2SO4), and concentrated by rotary
evaporation. The residue was purified by column chromatography
(silica gel, n-hexane–EtOAc, 10:1 to 4:1) to give (–)-3 (10.2 g,
99%) as a colorless solid; >99% ee {HPLC (Chiralcel OD, 0.46
cm × 25 cm, n-hexane–i-PrOH, 95:5 with 0.1% Et2NH, flow
rate = 1.0 mL/min): tR = 6.2 [(+)-3], 10.0 min [(–)-3]}; mp 38.8–
39.2 °C.
[a]D27 –43.6 (c 0.50, DMF).
1H NMR (400 MHz, CDCl3): d = –0.27 (s, 3 H), 0.04 (s, 3 H), 0.82
(s, 9 H), 1.15 (td, J = 13.0, 12.5 Hz, 1 H), 1.43 (dd, J = 13.2, 12.5,
Hz, 1 H), 1.95–2.04 (m, 2 H), 2.45 (s, 3 H), 2.53 (dd, J = 13.2, 6.3
Hz, 1 H), 2.64–2.67 (m, 1 H), 3.32 (t, J = 13.2 Hz, 1 H), 3.84 (dd,
J = 9.3, 6.3 Hz, 1 H), 3.91 (dd, J = 9.3, 5.4 Hz, 1 H), 5.04 (d, J = 6.8
Hz, 1 H), 7.06 (dd, J = 7.3, 4.9 Hz, 1 H), 7.34 (d, J = 8.3 Hz, 2 H),
7.36 (dd, J = 7.3, 1.5 Hz, 1 H), 7.77 (d, J = 8.3 Hz, 2 H), 8.27 (dd,
J = 4.9, 1.5 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = –5.3, –5.0, 18.0, 21.6, 25.8, 30.7,
31.7, 35.4, 35.5, 75.8, 77.1, 122.6, 127.9, 129.8, 133.0, 137.5,
137.6, 144.7, 145.6, 161.6.
HRMS (ESI): m/z [M + H]+ calcd for C24H36NO4SiS: 462.2134;
found: 462.2135.
cis-Isomer 35
Colorless crystals; mp 90.3–91.0 °C.
1H NMR (400 MHz, CDCl3): d = 1.30 (t, J = 7.3 Hz, 3 H), 1.89 (td,
J = 12.2, 10.9 Hz, 1 H), 2.70 (ddd, J = 12.2, 5.9, 1.5 Hz, 1 H), 2.87–
2.96 (m, 1 H), 3.02–3.15 (m, 2 H), 4.21 (q, J = 7.3 Hz, 2 H), 4.78
(dd, J = 10.7, 5.4 Hz, 1 H), 7.17 (dd, J = 7.8, 4.9 Hz, 1 H), 7.47 (dd,
J = 7.8, 1.5 Hz, 1 H), 8.44 (dd, J = 4.9, 1.5 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 14.2, 30.5, 33.4, 37.6, 60.9, 68.7,
122.6, 129.3, 136.9, 147.0, 157.0, 174.0.
Anal. Calcd for C24H35NO4SiS: C, 62.44; H, 7.64; N, 3.03. Found:
C, 62.32; H, 7.53; N, 2.83.
HRMS (ESI): m/z [M + H]+ calcd for C12H16NO3: 222.1130; found:
222.1134.
Anal. Calcd for C12H15NO3: C, 65.14; H, 6.83; N, 6.33. Found: C,
65.12; H, 6.79; N, 6.19.
Ethyl 5,6,7,8-Tetrahydroquinoline-6-carboxylate (32)
To a stirred soln of propargylamine (324 g, 5.88 mol) and
NaAuCl4⋅2H2O (29.2 g, 73.4 mmol) in EtOH (2.5 L) was added a
soln of ethyl 4-oxocyclohexanecarboxylate (31, 500 g, 2.94 mol) in
EtOH (250 mL) at 60 °C. The mixture was stirred at reflux temper-
ature overnight and then cooled to r.t. and filtered through a pad of
Celite; the filtrate was concentrated by rotary evaporation. The res-
idue was used in the next step without further purification. Analyt-
ically pure 32 was obtained by column chromatography (silica gel,
n-hexane–EtOAc, 20:1 to 1:1) as a pale brown oil.
1H NMR (400 MHz, CDCl3): d = 1.23 (t, J = 7.0 Hz, 3 H), 1.89–
2.01 (m, 1 H), 2.23–2.33 (m, 1 H), 2.69–2.76 (m, 1 H), 2.89–3.05
(m, 4 H), 4.15 (q, J = 7.0 Hz, 2 H), 7.02 (dd, J = 7.4, 4.7 Hz, 1 H),
7.36 (dd, J = 7.4, 0.8 Hz, 1 H), 8.34 (dd, J = 4.7, 0.8 Hz, 1 H).
trans-Isomer 36
Analytically pure 36 was obtained by crystallization (i-Pr2O) as col-
orless needles; mp 106–107 °C.
1H NMR (400 MHz, CDCl3): d = 1.28 (t, J = 7.3 Hz, 3 H), 2.20
(ddd, J = 14.1, 9.8, 4.4 Hz, 1 H), 2.40 (dt, J = 14.1, 3.8 Hz, 1 H),
3.00–3.06 (m, 2 H), 3.08–3.17 (m, 1 H), 4.19 (q, J = 7.3 Hz, 2 H),
4.41 (br s, 1 H), 4.87 (t, J = 4.4 Hz, 1 H), 7.17 (dd, J = 7.8, 4.9 Hz,
1 H), 7.50 (dd, J = 7.8, 1.5 Hz, 1 H), 8.42 (dd, J = 4.9, 1.5 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 14.2, 30.6, 33.1, 35.1, 60.8, 67.0,
122.9, 130.2, 137.3, 147.4, 156.6, 174.9.
HRMS (ESI): m/z [M + H]+ calcd for C12H16NO3: 222.1130; found:
222.1129.
13C NMR (100 MHz, CDCl3): d = 14.2, 25.7, 30.8, 31.3, 39.4, 60.6,
121.2, 130.2, 136.8, 147.2, 156.0, 174.9.
HRMS (ESI): m/z [M + H]+ calcd for C12H16NO2: 206.1181; found:
206.1178.
Anal. Calcd for C12H15NO3: C, 65.07; H, 6.78; N, 6.17. Found: C,
65.12; H, 6.79; N, 6.19.
Ethyl trans-8-Hydroxy-5,6,7,8-tetrahydroquinoline-6-carboxy-
late (36) by Mitsunobu Reaction and Subsequent Alcoholysis
To a stirred soln of 35 (240 mg, 1.08 mmol) in THF (10 mL) were
Anal. Calcd for C12H15NO2·0.33H2O: C, 68.24; H, 7.47; N, 6.63.
Found: C, 68.18; H, 7.65; N, 6.80.
Synthesis 2009, No. 7, 1153–1162 © Thieme Stuttgart · New York