Synthesis of Substituted 1,2,3,4-Tetrahydroisoquinolines
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purchased from Fluka. Ethylmagnesium iodide was freshly prepared from ethyl iodide and
magnesium in Et2O and used immediately.
2-Benzyl-6-t-butyl-1,2,3,4,6,7,8,8a-octahydro-6-isoquinolinol (4aa, 4ab; C20H29NO)
A solution of 3.4 g (14.1 mmol) of enone 3 in dry THF (35 cm3) was cooled to 70ꢀC and treated
with 11 cm3 (16.5 mmol, 1.5 M solution in pentane) of t-butyllithium under argon. After stirring for
1 h at 70ꢀC, the mixture was allowed to warm to room temperature. Then the mixture was poured
onto ice/aqueous NH4Cl solution (150 cm3), diluted with Et2O (40 cm3), and stirred vigorously. The
aqueous layer was separated and extracted with Et2O (2 Â 40 cm3). The combined organic layers
were washed with brine, dried over MgSO4, and concentrated in vacuo to give crude 4a (mixture
of stereoisomers). The crude product thus obtained was used in the subsequent dehydratization/
aromatization reaction without further puri®cation or chromatographed (SiO2, ethyl acetate:toluene
1:1; additional TLC detection using CH2Cl2:MeOH 9:1 allows ready discrimination between 4ab
and starting material 3) to obtain the pure isomers 4aa (OH in equitorial, t-butyl in axial position)
and 4ab (OH in axial, t-butyl in equitorial position) in 39 and 12% yield, respectively.
4aa: Yellow oil; 1H NMR (500 MHz, CDCl3): ꢀ 7.20±7.35 (m, 5H), 5.58 (q, J 2 Hz, 1H, H-5),
3.50 (s, 2H), 2.96 (ddd, J 2.0 5.5 11 Hz, 1H, H-1eq), 2.92 (dddd, J 2 2.5 5 10.5 Hz,
1H, H-3eq), 2.37 (dddd, J 2 5 12 14, 1H, H-4ax), 2.15±2.23 (m, 1H, H-8a), 2.12 (dt,
J 2.5 14 Hz, 1H, H-4eq), 1.92 (ddd, J 3 10.5 12, 1H, H-3ax), 1.53±1.70 (m, 4H, H-1ax,
H-7ax, H-7eq, H-8), 1.32±1.42 (m, 1H, H-8), 0.93 (s, 9H) ppm.
1
4ab: Yellow oil; H NMR (500 MHz, CDCl3): ꢀ 7.25±7.35 (m, 5H), 5.59 (dd, J 2 2.6 Hz,
1H, H-5), 3.50 (s, 2H), 2.99 (dddd, J 2 2.5 4.5 10.5 Hz, 1H, H-3eq), 2.81 (ddd,
J 2.0 4.5 10.5 Hz, 1H, H-1eq), 2.34 (dddd, J 2.6 4.5 12.5 13, 1H, H-4ax), 2.25±2.29
(m, 1H, H-8a), 2.07 (dt, J 2.5 13 Hz, 1H, H-4eq), 1.98 (dddd, J 4 7 12 14 Hz, 1H, H-8ax),
1.87 (ddd, J 2.5 10.5 12.5, 1H, H-3ax), 1.79 (dd, J 10.5 11.5 Hz, 1H, H-1ax), 1.69 (ddd,
J 4 12 13.5 Hz, 1H, H-7ax), 1.52 (ddd, J 4 5.5 13.5 Hz, 1H, H-7eq), 1.34 (dddd,
J 3 4 5.5 14 Hz, 1H, H-8eq), 0.97 (s, 9H) ppm; NOEs observed from t-butyl to H-7ax, H-
7eq, and H-5: 9.4, 5.5, and 17%.
2-Benzyl-6-t-butyl-5-methyl-1,2,3,4,6,7,8,8a-octahydro-6-isoquinolinol (4ba, 4bb; C21H31NO)
Following the procedure described for the synthesis of 4a, reaction of enone 5 with t-butyllithium gave
two isomeric alcohols as yellowish oils after silica gel chromatography (toluene:ethylacetate 2:1).
4ba (OH in equitorial, t-butyl in axial position): 48% yield; 1H NMR (500 MHz, CDCl3):
ꢀ 7.25±7.35 (m, 5H), 3.50 (d, J 13.1 Hz, 1H, Ph-CH2N), 3.46 (d, J 13.1 Hz, 1H, Ph-CH2N),
2.84±2.93 (m, 2H, H-3eq, H-1eq), 2.63 (dt, J 2.5 14.5 Hz, 1H, H-4eq), 2.13±2.20 (m, 1H, H-8a),
1.99±2.08 (m, 1H, H-4ax), 1.89 (ddd, J 2.5 10.6 13.4 Hz, 1H, H-3ax), 1.78±1.84 (m, 1H, H-7ax),
1.77 (t, J 1.8 Hz, 3H, CH3), 1.59±1.70 (m, 3H, H-1ax, H-7eq, H-8eq), 1.10±1.17 (m, 1H, H-8ax),
0.98 (s, 9H) ppm.
4bb (OH in axial, t-butyl in equitorial position): 18% yield; 1H NMR (500 MHz, CDCl3):
ꢀ 7.23±7.36 (m, 5H), 3.50 (d, J 13.1 Hz, 1H, Ph-CH2N), 3.46 (d, J 13.1 Hz, 1H, Ph-CH2N),
2.97 (dddd, J 2.1 2.5 4.7 10.8 Hz, 1H, H-3eq), 2.83 (ddd, J 2.1 4.5 10.6 Hz, 1H, H-1eq),
2.55 (dt, J 2.5 13.9 Hz, 1H, H-4eq), 2.26±2.34 (m, 1H, H-8a), 2.20±2.24 (m, 1H, H-7eq or H-8eq),
2.02±2.09 (m, 1H, H-4ax), 1.88 (ddd, J 2.5 10.8 13.4, 1H, H-3ax), 1.76 (dd, J 1.3 2.1 Hz,
3H, CH3), 1.57±1.68 (m, 2H, H-7eq or H-8eq, H-1ax), 1.32±1.46 (m, H-7ax, H-8ax), 1.01 (s, 9H) ppm.
2-Benzyl-6-t-butyl-1,2,3,4-tetrahydroisoquinoline (6a; C20H25N)
A mixture of 1.4 g (4.7 mmol) of crude 4a, 1.35 g (5.17 mmol) of triphenylmethanol, and 12 cm3
tri¯uoroacetic acid was heated to re¯ux for 6 h, cooled, and poured onto ice/water (100 cm3). The