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A. A. Orden et al. / Tetrahedron: Asymmetry 24 (2013) 744–749
2-(3-(Benzyloxy)phenyl)-N-(1-(3,4-dimethoxyphenyl)propan-2-
yl)-N-methylacetamide rac-4b
CH2-CH), 3.46–3.54 (1H, m, CH-CH3), 3.76 (3H, s, OCH3), 3.94 (1H,
dd, J = 4.8, 8.4 Hz, Ph-CH2-CH), 6.46–6.62 (4H, m, Ar), 4.70–6.72
(2H, m, Ar), 7.07–7.13 (1H, m, Ar). 13C NMR (CDCl3, 75 MHz):
d = 18.7, 31.8, 35.7, 42.2, 47.3, 55.1, 55.2, 66.0, 111.6, 113.2,
113.8, 116.3, 121.8, 128.4, 129.2, 129.3, 134.8, 141.2, 156.6,
157.9. HRMS calculated for C19H23NO2 [M+ꢀH]: 296.1650; found:
296.1646. Retention time on HPLC (achiral C18 column, details
see above): 25.9 min.
Obtained as a brownish liquid (1.60 g, 58%). The NMR spectra
revealed the presence of a mixture of the cis- and trans-isomers.
1H NMR (CDCl3, 300 MHz): d = 1.05 (3H, d, J = 6.5 Hz, CH-CH3),
1.11 (3H, d, J = 6.7 Hz, CH-CH3), 2.56–2.62 (2H, m, Ph-CH2-CH),
2.68–2.70 (2H, m, Ph-CH2-CH), 2.75 (3H, s, N-CH3), 2.89 (3H, s, N-
CH3), 3.39 (2H, s, Ph-CH2-CO), 3.60 (2H, s, Ph-CH2-CO), 3.83 (6H,
s, OCH3), 3.84 (6H, s, OCH3), 4.03–4.00 (1H, m, CH), 5.04 (2H, s,
Ph-CH2-O), 5.08 (2H, s, Ph-CH2-O), 5.11–5.08 (1H, m, CH), 6.86–
6.49 (12H, m, Ar), 7.44–7.14 (12H, m, Ar). 13C NMR (CDCl3,
75 MHz): d = 17.2, 18.4, 26.7, 29.5, 39.7, 40.3, 41.3, 41.9, 49.3,
55.0, 55.8, 55.9, 56.0, 69.8, 69.9, 111.0, 111.4, 112.0, 112.1, 113.1,
115.0, 115.2, 120.9, 121.0, 121.1, 121.2, 127.5, 127.6, 128.0,
128.6, 129.7, 130.9, 131.0, 136.6, 137.0, 137.1, 147.5, 147.8,
148.8, 149.0, 159.0, 159.1, 170.7, 170.8. HRMS calculated for
cis-1-(3-Hydroxybenzyl)-6,7-dimethoxy-2,3-dimethyl-1,2,3,4-
tetrahydroisoquinoline cis-5b
Obtained as white crystals, which were not soluble in CH2Cl2 or
CHCl3. Yield 246 mg (17%). Mp: 159–161 °C. 1H NMR (CDCl3,
300 MHz, analyzed as a benzyloxy derivative) d = 1.22 (3H, d,
J = 5.7 Hz, CH3-CH), 2.46 (3H, s, NCH3), 2.55–2.48 (3H, m overlap
Ph-CH2-CH-CH3), 2.89–2.75 (1H, m, Ph-CH2-CH), 3.14 (1H, dd,
J = 3.3, 14.5 Hz, Ph-CH2-CH), 3.58 (3H, s, OCH3), 3.78–3.75 (1H, m,
Ph-CH2-CH), 3.83 (3H, s, OCH3) 4.99 (2H, s, Ph-CH2-O), 6.20 (1H,
s, Ar), 6.53 (1H, s, Ar), 6.82–6.69 (3H, m, Ar). 7.14 (1H, t,
J = 7.8 Hz, Ar), 7.44–7.30 (5H, m, Ar). 13C NMR (CHCl3, 75 MHz):
d = 21.7, 37.1, 40.4, 44.9, 55.4, 55.8, 67.1, 70.0, 76.7, 77.1, 77.6,
110.4, 112.4, 116.6, 122.9, 127.5, 127.9, 128.1, 128.6, 128.9,
129.6, 137.2, 141.6, 146.6, 147.0, 158.5. HRMS calculated for
C
27H31NO4 [M+]: 433.2253; found: 433.2254.
4.6. General procedure for the preparation of rac-5a–b
To a solution of 4a–b (7.18 mmol of 4a or 4.32 mmol of 4b) in
dry acetonitrile (70 mL), POCl3 (3.23 g, 21.1 mmol) was added
and the mixture was refluxed for 3 h under an argon atmosphere.
The solvent and excess POCl3 were evaporated under reduced pres-
sure and the residue was dissolved in dry methanol, put under ar-
gon and cooled to 0 °C using an ice bath. Next, NaBH4 (1.98 g,
52.2 mmol) was added in portions to the stirred mixture. The ice
bath was then removed and stirring was continued for 14 h at
room temperature. The solvent was evaporated and the residue
was treated with a half-saturated Na2CO3 solution (100 mL). The
product was extracted with CH2Cl2 (3 ꢃ 50 mL), the combined or-
ganic phases were dried over Na2SO4 and evaporated under re-
duced pressure to give a pale yellowish liquid. Analysis by TLC
showed two products, which were separated by flash chromatog-
raphy (silica; EtOAc/MeOH = 95/5). Each product was treated with
Pd (10% on activated charcoal; 200 mg), acetic acid (470 mg,
7.8 mmol), and dry methanol (20 mL) and stirred under an H2
atmosphere (balloon) for 16 h. The mixture was filtered through
Celite, washed with methanol (50 mL), and evaporated under re-
duced pressure. The residue was dissolved in CH2Cl2 and washed
with a half-saturated NaHCO3 solution (40 mL). The organic phase
was dried over Na2SO4 and evaporated under reduced pressure.
The residue was purified by silica gel flash chromatography
(EtOAc/MeOH = 95/5).
C
20H25NO3 [M+ꢀH]: 326.1756; found: 326.1735.
trans-1-(3-Hydroxybenzyl)-6,7-dimethoxy-2,3-dimethyl-
1,2,3,4-tetrahydroisoquinoline trans-5b
Obtained as yellow crystals. Yield 703 mg (49%). Mp: 82–84 °C.
1H NMR (CDCl3, 300 MHz) d = 1.76 (3H, d, J = 6.0 Hz, CH3-CH), 2.99
(3H, s, NCH3), 3.16–3.07 (2H, m, Ph-CH2-CH-CH3), 3.34–3.22 (1H,
m, Ph-CH2-CH), 3.77–3.69 (1H, m, Ph-CH2-CH), 3.83 (3H, s, OCH3)
4.52–4.36 (4H, overlap s + m, OCH3, Ph-CH2-CH-CH3), 4.57–4.54
(1H, m, Ph-CH2-CH), 6.25 (1H, s, Ar), 6.95 (1H, s, Ar), 7.13–7.03
(3H, m, Ar), 7.58–7.53 (1H, m, Ar). 13C NMR (CHCl3, 75 MHz):
d = 19.2, 31.5, 36.1, 42.1, 47.3, 55.4, 55.8, 66.6, 111.1, 112.4,
116.5, 122.7, 125.8, 142.0, 146.3, 147.3, 158.7. HRMS calculated
for C20H25NO3 [M+ꢀH]: 326.1756; found: 326.1724.
4.7. General procedure for the preparation of rac-cis-5a–b
To a solution of 4a–b (50 mg, 0.12 mmol) in dry acetonitrile
(3 mL), POCl3 (56 mg, 0.36 mmol) was added and the mixture
was refluxed for 3 h under an argon atmosphere. The solvent and
excess POCl3 were evaporated under reduced pressure and the res-
idue was dissolved in dry methanol (3 mL). Next, Pd (10% on acti-
vated charcoal; 30 mg) was added and the mixture was stirred
under an H2 atmosphere (balloon) for 5 h. The solids were removed
by filtration through Celite, washed with MeOH (10 mL), and the
solvent was evaporated under reduced pressure. The residue was
dissolved in CH2Cl2 and washed with a half-saturated NaHCO3
solution (15 mL). The organic phase was dried over Na2SO4 and
evaporated under reduced pressure. The products of the reaction
were analyzed by GC–MS and TLC (EtOAc/MeOH = 95/5) and their
Rf and tr compared to cis-5a and cis-5b obtained as described
above.
cis-1-(3-Hydroxybenzyl)-6-methoxy-2,3-dimethyl-1,2,3,4-
tetrahydroisoquinoline cis-5a
Obtained as white crystals, which were not soluble in CH2Cl2 or
CHCl3. Yield 298 mg (14%). Mp: 125–126 °C. 1H NMR (MeOD,
300 MHz): d = 1.24 (3H, d, J = 5.7 Hz, CH3-CH), 2.41 (3H, s, NCH3),
2.52–2.58 (3H, m overlap, Ph-CH2-CH-CH3), 2.83 (1H, dd, J = 7.5,
13.8 Hz, Ph-CH2-CH), 3.06 (1H, dd, J = 4.5, 13.8 Hz, Ph-CH2-CH),
3.73 (3H, s, OCH3), 3.83 (1H, dd, J = 4.5, 7.5 Hz, Ph-CH2-CH), 6.57–
6.62 (5H, m, Ar), 6.71–6.75 (1H, m, Ar), 7.01–7.06 (1H, m, Ar). 13C
NMR (MeOD, 75 MHz): d = 20.0, 36.5, 38.6, 43.7, 54.1, 55.7, 66.7,
111.3, 111.9, 112.5, 116.2, 120.6, 127.8, 128.5, 129.5, 136.7,
141.2, 156.7, 158.0. HRMS calculated for C19H23NO2 [M+ꢀH]:
296.1650; found: 296.1664. Retention time on HPLC (achiral C18
column, details see above): 26.2 min.
4.8. Preparation of (R)-3a–b
To a solution of (R)-2a (760 mg, 4.6 mmol) in CH2Cl2 (20 mL)
were added triethylamine (512 mg, 5.06 mmol) and ethyl chloro-
formate (599 mg, 5.52 mmol) and the mixture was stirred for 3 h
at room temperature. Water (25 mL) was added, the phases were
separated, and the aqueous phase was extracted with CH2Cl2
(2 ꢃ 15 mL). The combined organic phases were dried over Na2SO4
and evaporated under reduced pressure to give the corresponding
carbamates.
trans-1-(3-Hydroxybenzyl)-6-methoxy-2,3-dimethyl-1,2,3,4-
tetrahydroisoquinoline trans-5a
Obtained as a yellow solid foam. Yield 946 mg (44%). Mp: 46–
49 °C. 1H NMR (CDCl3, 300 MHz): d = 1.28 (3H, d, J = 6.6 Hz, CH3-
CH), 2.39 (3H, s, NCH3), 2.66–2.70 (2H, m, Ph-CH2-CH), 2.82 (1H,
dd, J = 8.4, 13.2 Hz Ph-CH2-CH), 3.25 (1H, dd, J = 4.8, 13.2 Hz Ph-