The Journal of Organic Chemistry
Article
(S)-(+)-1-(3,4-Dimethoxybenzyl)-2-formyl-6,7-dimethoxy-
1,2,3,4-tetrahydroisoquinoline. Amine 4d (234 mg, 681 μmol)
was dissolved in ethyl formate (30 mL), and the mixture was refluxed
for 2 h.49 The solvent was removed in vacuo, and the crude product
was purified by column chromatography (cyclohexane/EtOAc/HNEt2
= 6:6:1) to yield the title compound (252 mg, quant) as a light yellow
foam: mp 133.5−134 °C; Rf = 0.30 (cyclohexane/EtOAc/HNEt2 =
6:3:1); [α]25 = +84.2 (c = 0.5, CHCl3) (lit.48 [α]24 = +86.3 (c =
by addition of aq NaOH (1 M), and the product was extracted with
EtOAc (3 × 5 mL). The combined organic layers were dried over
Na2SO4, and the solvent was removed in vacuo. The crude product
(13.8 mg, yellow oil) was purified by preparative TLC (cyclohexane/
EtOAc/HNEt2 = 5:3:1) to furnish the title compound (9.8 mg, 0.22
μmol, 56%) as a colorless oil: mp 156.5−158 °C (lit.30 146 °C); Rf =
0.36 (cyclohexane/EtOAc/HNEt2 = 6:3:1); [α]25 = +40.1 (c = 0.5,
D
CHCl3) (lit.52 [α]D = +44 (CHCl3)); 1H NMR (400 MHz, CDCl3) δ
= 6.98 (s, 1H, H-3′), 6.60 (s, 1H, H-6′), 6.57 (s, 1H, H-5), 5.94 (s, 1H,
H-8), 3.86−3.84 (m, 1H, H-1), 3.83, 3.83, 3.72, 3.53 (4s, 4 × 3H,
OCH3), 3.40−3.22 (m, 2H, H-3b, Ar-CHb), 2.95−2.90 (m, 3H, H-3a,
Ar-CHa, H-4a), 2.79−2.71 (m, 1H, H-4b), 2.60 (s, 3H, N-CH3) ppm;
IR (NaCl) ν = 2999, 2932, 2837, 2797, 1607, 1506, 1462, 1379, 1254,
D
D
1
1.02, CHCl3)); H NMR (400 MHz, CDCl3, 1:1 mixture of rotamers
A and B) δ = 8.14 (CHOB), 7.70 (CHOA), 6.81 (d, J = 8.5 Hz, 1H, H-
5′B), 6.74 (d, J = 8.2 Hz, 1H, H-5′A), 6.66 (dd, J = 8.3 Hz, J = 2.3 Hz,
1H, H-6′B), 6.62−6.59 (m, 4H, H-8B, H-8A, H-2′A, H-6′A), 6.57 (s, 1H,
H-5B), 6.50 (s, 1H, H-5A), 6.33 (s, 1H, H-2′B), 5.52 (t, J = 6.5 Hz, 1H,
H-1B), 4.57 (dd, J = 8.9 Hz, J = 5.0 Hz, 1H, H-1A), 4.48 (ddd, J = 12.8
1218, 1161, 1137, 1101, 1029, 859, 800 cm−1 13C NMR, HMBC,
;
Hz, J = 6.3 Hz, J = 2.1 Hz, 1H, H-3A ), 3.87 (s, 3H, OCH3), 3.86 (s,
HSQC (100.6 MHz, CDCl3) δ = 148.3, 148.1, 147.9, 146.7 (C-6, C-7,
C-4′, C-5′), 130.5 (C-4a), 125.5 (C-8a), 115.4, 115.2 (C-3′, C-6′),
115.1 (C-2′), 111.3 111.2 (C-5, C-8), 62.1 (C-1), 56.3, 56.2, 56.0, 55.7
(4 × OCH3), 46.7 (C-3), 42.4 (N−CH3), 40.6 (Ar-CH2), 24.8 (C-4)
ppm; ESI-MS m/z = 436.1 (100) [M + H]+ ESI-HRMS calcd for
[C21H26BrNO4 + H]+ 436.1123, found 436.11102.
b
3H, OCH3), 3.85 (s, 3H, OCH3), 3,85 (s, 3H, OCH3), 3.84 (s, 3H,
OCH3), 3.84 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 3.69 (s, 3H,
OCH3), 3.56 (ddd, J = 13.0 Hz, J = 6.3 Hz, J = 2.2 Hz, 1H, H-3B ),
b
3.30−3.23 (m, 1H, Ar-CHBb), 3.17−2.77 (m, 7H, H-3A , Ar-CH2 , Ar-
A
a
CHB , H-3B , H-4A , H-4B ), 2.70 (mc, 1H, H-4A ), 2.60 (mc, 1H, H-
a
a
b
b
a
4B ) ppm; ESI-MS m/z = 344.1 (100) [M − CHO + H]+, 327.1 (32)
(+)-O-Tetramethylmagnolamine (9). In a flame-dried, argon-
flushed microwave reaction glass vessel were suspended (+)-armepa-
vine (5b, 10.7 mg. 34.3 μmol), bromide 8 (15 mg, 34,3 μmol),
Cs2CO3 (33,6 mg, 103 μmol), CuI (0.7 mg, 3.43 μmol), and N,N-
dimethylglycine (1.44 mg, 3,43 μmol) in dry DMF (0.25 mL). The
mixture was heated to 160 °C for 1 h by microwave irradiation
(monomode, IR-temperature control, maximum power 150 W). After
cooling and pressure equilibration, the reaction mixture was
coevaporated with toluene. The desired diaryl ether was purified by
column chromatography (cyclohexane/EtOAc/HNEt2 = 7:1:0.5).
After addition of petroleum ether, the crude product (brow oil)
crystallized as a beige solid (11.5 mg, 17.2 μmol, 50%): Rf = 0.4
(cyclohexane/EtOAc/HNEt2 = 6:3:1); mp 145.3−145.9 °C (lit.30
148−149.5 °C); [α]25 = +85.6 (c = 1, CHCl3) (lit.29 [α]25 = +86.2
a
[M + H]+, 394.1 (26) [M + Na]+; ESI-HRMS calcd for [C21H25NO5 +
Na]+ 394.1630, found 394.1620. The spectroscopic data match those
reported in the literature.48
(S)-(+)-1-(2-Bromo-4,5-dimethoxybenzyl)-2-formyl-6,7-di-
methoxy-1,2,3,4-tetrahydroisoquinoline (7). (S)-(+)-1-(3,4-Di-
methoxybenzyl)-2-formyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquino-
line (252 mg, 679 μmol) was dissolved in CH2Cl2 (2 mL), and
saturated aq NaHCO3 (0.5 mL) was added. After addition of Br2 (38.2
μL, 746 μmol) at 0 °C, the mixture was stirred for 4 h while gradually
warming to room temperature.50 The mixture was quenched by
saturated aq Na2S2O3 (5 mL) and extracted with CH2Cl2 (4 × 5 mL).
The combined organic layers were washed with saturated aq NaHCO3
and brine (25 mL each) and dried over Na2SO4. Concentration in
vacuo furnished the title compound (294 mg, 653 μmol, 96%) as a
light brown oil: Rf = 0.27 (cyclohexane/EtOAc/HNEt2 = 5:3:1);
D
D
(c = 1.02, CHCl3)); IR (NaCl) ν = 2999, 2930, 2854, 2836, 1609,
1
1502, 1464, 1289, 1253, 1217, 1102, 1005, 912, 861 cm−1; H NMR,
[α]25 = +129.4 (c = 1, CHCl3); IR (NaCl) ν = 3067, 2999, 2939,
3
COSY (400 MHz, CDCl3) δ = 7.01 (d, J = 8.8 Hz, 2H, H-2′, H-6′),
D
1
2843, 1669, 1508, 1438, 1258, 1220, 1165, 1114, 1030, 859 cm−1; H
6.76 (d, 3J = 8.8 Hz, 2H, H-3′, H-5′), 6.58 (s, 1H, H-2‴), 6.54 (s, 2H,
H-5, H-5′′), 6.51 (s, 1H, H-5‴), 6.13, 6,12 (2 s, 2H, H-8, H-8′′), 3.83,
3.82, 3.76, 3.76 (4 s, 12H, 4 × OCH3), 3.72−3.72, 3.69−3.67 (2 m,
2H, H-1, H-1′′), 3.61, 3.58 (2 s, 6H, 2 × OCH3), 3.20−3.09 (m, 3H,
H-3b, H-3b′′, Ar-CHb), 3.00 (dd, J = 13.4 Hz, J = 6.0 Hz, 1H, Ar-CHb′′),
2.85−2.67 (m, 6H, H-3a, H-3a′′, Ar-CHa, Ar-CHa′′, H-4b, H-4b′′), 2.60−
2.53 (m, 2H, H-4a, H-4a′′) ppm;13C NMR, HMBC, HSQC (100.6
MHz, CDCl3) δ = 157.2 (C-1′), 148.2, 147.4, 147.4, 147.2, 146.6,
146.5 (C-6, C-7, C-6′′, C-7′′, C-3‴, C-4‴), 141.5 (C-1‴), 133.6 (C-4′),
131.0 (C2′, C-6′), 129.8, 129.3 (C-4a, C-4a′′), 126.3, 126.3 (C-8a, C-
8a′′), 123.9 (C-6‴), 116.0 (C-3′, C-5′), 114.8 (C-2‴), 111.3, 111.2,
111.1, 111.0 (C-5, C-5′′, C-8, C-8′′), 106.1 (C-5‴), 64.9, 63.4 (C-1, C-
1′′), 56.3, 56.2, 55.9, 55.8 55.7, 55.7 (6 × OCH3), 47.0, 46.9 (C-3, C-
3′′), 42.9, 42.8 (2 × N−CH3), 40.7, 35.0 (Ar-CH2, Ar-CH2′′), 28.8,
25.4 (C-4, C-4′′) ppm; ESI-MS m/z = 335.1 (100) [M + 2H]2+; ESI-
HRMS calcd for [C40H48N2O7 + H]+ 669.3540, found 669.3533. The
spectroscopic data match those reported in the literature.30
NMR, COSY (400 MHz, CDCl3, 2:1 mixture of rotamers A and B) δ
= 8.10 (s, 1H, CHOB), 7.64 (s, 1H, CHOA), 7.06 (s, 1H, H-3′A), 6.97
(s,1H, H-3′B), 6.73 (s, 1H, H-8A), 6.70 (s, H1, H-6′B), 6.63 (s, 1H, H-
5A), 6.57 (s, 1H, H-5B), 6.48 (s, 1H, H-6′A), 6.43 (s, 1H, H-8B), 5.65 (t,
J = 6.4 Hz, 1H, H-1B), 4.75−4.71 (dd, J = 9.9 Hz, J = 4.1 Hz, 1H, H-
1A), 4.53−4.45 (ddd, J = 13.0 Hz, J = 6.1 Hz, J = 2.0 Hz, 1H, H-3A ),
b
A
A
A
3.88 (s, 3H, OCH3 ), 3.87 (s, 3H, OCH3 ), 3.84 (s, 9H, OCH3 , 2 ×
B
A
B
OCH3 ), 3.80 (s, 3H, OCH3 ), 3.73 (s, 3H, OCH3 (C-4′), 3.70 (s,
3H, OCH3 ), 3.66−3.62 (m, 1H, H-3B ), 3.59−3.51 (m, 1H, H-3B ),
B
3.33−3.26 (m, 1H, Ar-CHBb), 3.25−3.19 (m, 2H, Ar-CHAb, H-3Aa),
b
a
3.15−3.10 (m, 1H, Ar-CHBa), 3.03−2.98 (m, 1H, Ar-CHAa), 2.94−
2.87 (m, 2H, H-4A , H-4B ) 2.78−2.72 (m, 2H, H-4A , H-4B ) ppm;
b
b
a
a
13C NMR, HMBC, HSQC (100.6 MHz, CDCl3, 2:1 mixture of
rotamers A and B) δ = 161.7 (CHOA), 161.6 (CHOB), 149.3 (C-5′A),
149.0 (C-4′A), 148.8 (C-7A), 148.8 (C-5′B), 148.6 (C-4′B), 148.5 (C-
7B), 148.1 (C-6A), 148.0 (C-6B), 129.5 (C-1′B), 129.0 (C-1′A), 127.7
(C-4aA), 127.5 (C-4aB), 126.7 (C-8aB), 126.5 (C-8aA), 116.2 (C-3′A),
115.7 (C-3′B), 115.7 (C-2′A), 115.0 (C-6′A), 114.8 (C-2′B), 114.4 (C-
6′B), 112.0 (C-5A), 111.8 (C-5B), 110.8 (C-8B), 110.3 (C-8A), 57.3 (C-
(S)-(−)-1-(4-Bromobenzyl)-6,7-dimethoxy-1,2,3,4-tetrahy-
droisoquinoline (4e). The title compound was prepared according
to the general procedure from KHMDS (914 mg, 4.58 mmol) in dry
THF (10 mL), 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-car-
bonitrile 1 (500 mg, 2.29 mmol) in dry THF (15 mL), 4-bromobenzyl
bromide (630 mg, 2.52 mmol) in dry THF (10 mL). The mixture was
stirred for 3.3 h at −78 °C. Workup yielded a light yellow oil (1.016
g): Rf = 0.75 (cyclohexane/EtOAc/HNEt2 = 6:3:1);1H NMR (400
1A), 56.6, 56.5, 56.3, 56.1 (4 × OCH3 ), 56.5, 56.4, 56.3, 56.2 (4 ×
A
OCH3 ), 51.2 (C-1B), 43.5 (Ar-CH2 ), 41.4 (Ar-CH2 ), 40.9 (C-3B),
34.7 (C-3A), 29.5 (C-4B), 28.1 (C-4A) ppm; ESI-MS m/z = 451.0
(100) [M + H]+, 472.0 (40) [M + Na]+ ESI-HRMS calcd for
[C21H24BrNO5 + H]+ 450.0916, found 450.0930.
B
A
B
3
3
MHz, CDCl3) δ = 7.39 (d, J = 8.0 Hz, 2H, H-3′ H-5′), 7.18 (d, J =
8.0 Hz, 2H, H2′, H-6′), 6.97 (s, 1H, H-5), 6.67 (s, 1H, H-8), 4.17 (s,
2H, Ar-CH2), 3.91 (s, 3H, OCH3), 3.76−3.67 (m, 5H, 2H, OCH3, H2-
(S)-(+)-1-(2-Bromo-4,5-dimethoxybenzyl)-2-methyl-6,7-di-
methoxy-1,2,3,4-tetrahydroisoquinoline (8). In a flame-dried
round-bottom flask, 7 (18.2 mg, 40.4 μmol) was dissolved in dry
THF (2 mL) under argon atmosphere. BH3·THF (1 M in THF, 40.4
μL) was slowly added at 0 °C, and the mixture was stirred for 1.5 h at
room temperature.51 After addition of aq HCl (1 M, 5 mL), the
mixture was heated to 100 °C for 4 h. The cooled reaction mixture was
washed with EtOAc (2 × 5 mL), the aqueous layer was made alkaline
3
3), 2.75 (t, J = 7.5 Hz, 2H, H2-4) ppm. The asymmetric transfer
hydrogenation was performed according to the general procedure
using triethylamine (47.8 μL, 434 μmol), dichloro-p-cymene-
ruthenium(II) dimer (21.6 mg, 34.3 μmol), and (1R,2R)-N-(4-
toluenesulfonyl)-1,2-diphenylethylenediamine (25.2 mg, 68.8 μmol) in
9782
dx.doi.org/10.1021/jo201871c|J. Org. Chem. 2011, 76, 9777−9784