578 J . Org. Chem., Vol. 61, No. 2, 1996
Matulenko and Meyers
trated in vacuo to provide 5.71 g (98%) of amide 12: white
solid; mp 99-101 °C; Rf 0.30 (EtOAc). 1H NMR (300 MHz,
C6D6): δ 7.08 (d, 1 H, J ) 1.8 Hz), 6.99 (dd, 1 H, J ) 8.2, 1.8
Hz), 6.49 (m, 1 H), 3.35 (s, 3 H), 3.37 (s, 3 H), 2.70 (br s, 6 H).
13C NMR (75 MHz, CDCl3): δ 171.25 (s), 149.93 (s), 148.63
(s), 128.46 (s), 120.03 (d), 110.71 (d), 110.21 (d), 55.79 (q), 39.57
(q), 35.36 (q). IR (thin film): 3000, 2936, 1629 cm-1. Anal.
Calcd for C11H15NO3: C, 63.13; H, 7.24. Found: C, 63.08; H,
7.33.
at 0 °C was added the formamidine as a solution in THF (10.0
mL with 2 × 2 mL rinses). After 0.5 h at rt, the reaction was
quenched with Na2SO4‚10H2O, MgSO4 was added, and the
slurry was filtered through a 2 in. plug of Celite. The filtrate
was concentrated and the residue purified by bulb to bulb
distillation (100 °C oven temperature at 0.5 mmHg) to afford
4.15 g (48%) of exchange formamidine 17: colorless oil; Rf 0.26
23
(7:2:1 EtOAc:hexanes:Et3N); [R]D -96.5 (c 1.03, CHCl3). 1H
NMR (300 MHz, CDCl3): δ 7.19 (s, 1 H), 3.47 (dd, 1 H, J )
9.4, 4.2 Hz), 3.30 (s, 3 H), 3.30 (m, 1 H), 2.79 (s, 6 H), 2.75 (m,
1 H), 1.68 (m, 1 H), 0.83 (d, 3 H, J ) 3.9 Hz), 0.81 (d, 3 H, J
) 3.9 Hz). 13C NMR (75 MHz, CDCl3): δ 154.24 (d), 76.35 (t),
71.00 (d), 58.82 (q), 37.04 (q), 30.75 (d), 19.99 (q), 18.50 (q). IR
(thin film): 2956, 2925, 2873, 2822, 1655 cm-1. LRMS (GC-
MS): for C9H20N2O (M+): calcd 172.31, found 172.10.
3,4-Dim eth oxy-N,N-dim eth ylben zen em eth an am in e (28).
To a slurry of LiAlH4 (95%, 1.46 g, 36.6 mmol) in THF (25.0
mL) at rt was added amide 12 (3.04 g, 14.5 mmol) as a solution
in THF (50.0 mL), and the reaction mixture was heated to
reflux for 4 h. The gray slurry was cooled to rt, 100 mL of
Et2O added, and the mixture slowly quenched with Na2SO4‚
10H2O (15 g). After 0.5 h, the white slurry was filtered
through a 2 in. plug of Celite and the cake washed with several
portions of EtOAc. The solvent was removed in vacuo and the
residue purified by bulb to bulb distillation to give 2.78 g (98%)
of amine 28: colorless oil; bp 113 °C (3 mmHg);13 Rf 0.13
(EtOAc). 1H NMR (300 MHz, C6D6): δ 7.00 (d, 1 H, J ) 1.8
Hz), 6.89 (dd, 1 H, J ) 8.1, 1.8 Hz), 6.64 (d, 1 H, J ) 8.1 Hz),
3.46 (s, 3 H), 3.44 (s, 3 H), 3.31 (s, 2 H), 2.16 (s, 6 H). 13C
NMR (75 MHz, CDCl3): δ 148.80 (s), 147.98 (s), 131.52 (s),
121.09 (d), 111.92 (d), 110.61 (d), 64.14 (t), 55.76 (q), 45.23 (q).
Eth yl 6-(ch lor om eth yl)-2,3-d im eth oxyben zoa te (13).
To a solution of amine 28 (2.78 g, 14.2 mmol) in THF (35.0
mL) at 0 °C was added n-BuLi (2.18 M in hexanes, 7.40 mL,
16.1 mmol), and stirring was continued for 1 h. The mixture
was then cooled to -78 °C, ethyl chloroformate (3.00 mL, 3.41
g, 31.4 mmol) was added dropwise, and stirring was continued
for 10 min. The brown solution was warmed to rt and stirred
for an additional 12 h. The solvent was removed in vacuo and
the residue transferred to a separatory funnel with water (50
mL) and CH2Cl2 (150 mL). The layers were partitioned, and
the aqueous phase was extracted with CH2Cl2 (2 × 30 mL).
The organic layers were combined, dried (Na2SO4), and
concentrated in vacuo. The residue was purified by bulb to
bulb distillation to afford 1.91 g (52%) of desired benzyl
(S )-2-[[(1-(Me t h oxym e t h yl)-2-m e t h ylp r op yl)im in o]-
m et h yl]-5,6,7,8-t et r a h yd r o-1,3-d ioxolo[4,5-g]isoq u in o-
lin e (18). To a solution of exchange formamidine 17 (1.91 g,
11.1 mmol) and isoquinoline 15 (1.58 g, 8.92 mmol) in toluene
(9.0 mL) at rt was added ammonium sulfate (135 mg, 1.02
mmol), and the reaction was heated to reflux for 18 h open to
air. The brown mixture was cooled to rt and the solvent
removed in vacuo. The residue was purified by flash column
chromatography (elution with 6:3:1 EtOAc:hexanes:Et3N) to
provide 1.99 g (73%) of the desired valine methyl ether
formamidine 18: light yellow oil; Rf 0.53 (6:3:1 EtOAc:hexanes:
25
Et3N); [R]D -55.6 (c 1.21, CHCl3). 1H NMR (300 MHz,
CDCl3): δ 7.36 (s, 1 H), 6.57 (s, 1 H), 6.55 (s, 1 H), 5.87 (s, 2
H), 4.39 (ABq, 2 H, J AB ) 16.7 Hz, ∆νAB ) 23.3 Hz), 3.46 (m,
4 H), 3.31 (s, 3 H), 2.78 (m, 1 H), 2.73 (app t, 2 H, J ) 5.7 Hz),
1.71 (m, 1 H), 0.85 (d, 3 H, J ) 5.6 Hz), 0.82 (d, 3 H, J ) 5.6
Hz). 13C NMR (75 MHz, CDCl3): δ 153.57 (d), 146.10 (s),
145.98 (s), 127.65 (s), 126.59 (s), 108.55 (d), 106.34 (d), 100.70
(t), 76.30 (t), 71.49 (d), 58.99 (q), 46.79 (t), 44.43 (t), 30.85 (d),
29.20 (t), 20.10 (q), 18.74 (q). IR (thin film): 2956, 2884, 1649
cm-1
found 304.20.
.
LRMS (GC-MS) for C17H24N2O3 (M+): calcd 304.43,
(()-5,6,13,13a -Tetr a h yd r o-9,10-d im eth oxy-2,3-m eth yl-
en ed ioxy-8H-d iben zo[a ,g]qu in olizin -8-on e (21). To a so-
lution of 18 (211 mg, 0.69 mmol) in THF (15.0 mL) at -78 °C
was added n-BuLi (2.18 M in hexanes, 0.50 mL, 1.1 mmol),
and stirring was continued for 1 h. The dark red anion was
then cooled to -105 °C, and the electrophile 13 (198 mg, 0.765
mmol) was added dropwise as a solution in THF (5.0 mL). The
reaction temperature was raised to -90 °C, and the reaction
mixture was stirred for 5 h. The light yellow mixture was
quenched with MeOH (3 mL) and warmed to rt. The solvent
was removed in vacuo, the residue was taken up in EtOH (8.0
mL), and cooled to 0 °C, and the solution was treated with
N2H4‚H2O (2.0 mL) and AcOH (1.0 mL). The mixture was
warmed to rt and stirred for 12 h. The volatiles were removed
in vacuo, and the residue was purified by flash column
chromatography (elution with 3:1 EtOAc:hexanes) to provide
108 mg (44%) of the desired amide 21: white solid; mp 217-
218 °C;19 Rf 0.35 (3:1 EtOAc:hexanes). 1H NMR (300 MHz,
CDCl3): δ 6.97 (d, 1 H, J ) 8.3 Hz), 6.90 (d, 1 H, J ) 8.2 Hz),
6.64 (s, 1 H), 6.63 (s, 1 H), 5.92 (s, 2 H), 4.96 (m, 1 H), 4.66
(dd, 1 H, J ) 12.9, 2.8 Hz), 3.99 (s, 3 H), 3.86 (s, 3 H), 2.97
(dd, 1 H, J ) 15.2, 3.1 Hz), 2.83 (m, 4 H).
(()-5,8,13,13a -Tet r a h yd r o-9,10-d im et h oxy-6H -b en zo-
[g]-1,3-ben zod ioxolo[5,6-a ]qu in olizin e (Ca n a d in e (1)). To
a solution of 21 (49 mg, 0.14 mmol) in THF (2.5 mL) at rt was
added LiAlH4 (95%, 30 mg, 0.75 mmol). The mixture was
heated to reflux, stirred for 2 h, and then cooled to rt. The
gray slurry was carefully quenched with Na2SO4‚10H2O fol-
lowed by addition of MgSO4. The white slurry was filtered
through a 1 in. plug of Celite and the filtrate concentrated in
vacuo. The residue was purified by flash column chromatog-
raphy (elution with 3:1 EtOAc:hexanes) to give 46 mg (98%)
of canadine: light yellow solid; mp 172-173 °C;20 Rf 0.45 (3:1
EtOAc:hexanes). 1H NMR (300 MHz, CDCl3): δ 6.84 (d, 1 H,
J ) 8.4 Hz), 6.76 (d, 1 H, J ) 8.4 Hz), 6.71 (s, 1 H), 6.57 (s, 1
H), 5.89 (s, 2 H), 4.21 (d, 1 H, J ) 15.5 Hz), 3.83 (s, 6 H), 3.51
(d, 1 H, J ) 15.2 Hz), 3.51 (m, 1 H), 3.20 (dd, 1 H, J ) 15.6,
3.6 Hz), 3.10 (m, 2 H), 2.79 (dd, 1 H, J ) 15.6, 11.4 Hz), 2.60
(m, 2 H). 13C NMR (75 MHz, CDCl3): δ 150.24 (s), 146.10 (s),
145.87 (s), 145.01 (s), 130.80 (s), 128.60 (s), 127.77 (s), 127.64
1
chloride 13: light yellow oil; Rf 0.46 (1:1 EtOAc:hexanes). H
NMR (300 MHz, CDCl3): δ 7.09 (d, 1 H, J ) 8.5 Hz), 6.89 (d,
1 H, J ) 8.6 Hz), 4.59 (s, 2 H), 4.42 (q, 2 H, J ) 7.2 Hz), 3.86
(s, 3 H), 3.85 (s, 3 H), 1.39 (t, 3 H, J ) 7.2 Hz). 13C NMR (75
MHz, CDCl3): δ 166.63 (s), 153.05 (s), 146.67 (s), 129.03 (s),
127.29 (s), 125.78 (d), 113.26 (d), 61.55 (t), 61.49 (q), 55.88 (q),
43.56 (t), 14.17 (q). IR (thin film): 2980, 2941, 2906, 2840,
1732 cm-1
.
5,6,7,8-Tetr a h yd r o-1,3-d ioxolo[4,5-g]isoqu in olin e (15).
To a solution of 1415 (2.30 g, 13.9 mmol) in formic acid (14.0
mL) at 50 °C was added paraformaldehyde (419 mg, 13.6
mmol). After 30 h, the reaction was cooled to rt, the solvent
removed in vacuo, and the residue transferred to a separatory
funnel with CH2Cl2 (150 mL). The organic phase was washed
with 1 M NaOH (2 × 50 mL), and the resulting aqueous layers
were back extracted with CH2Cl2 (2 × 50 mL). The layers were
combined, the solvent was removed in vacuo, and the residue
was taken up in 10% HCl and washed with EtOAc. The
aqueous layer was made basic with 1 M NaOH and extracted
with CH2Cl2 (5 × 100 mL), and the organic layers were
combined, dried (Na2SO4), and concentrated in vacuo to give
1.87 g (76%) of the desired tetrahydroisoquinoline 15: white
solid; mp 78-80 °C; Rf 0.16 (4:2:2:1 CH2Cl2:EtOAc:hexanes:
Et3N). 1H NMR (300 MHz, CDCl3): δ 6.52 (s, 1 H), 6.44 (s, 1
H), 5.85 (s, 2 H), 3.87 (s, 2 H), 3.05 (app t, 2 H, J ) 5.9 Hz),
2.66 (app t, 2 H, J ) 5.4 Hz), 1.98 (br s, 1 H). 13C NMR (75
MHz, CDCl3): δ 145.77 (s), 145.61 (s), 128.71 (s), 127.53 (s),
108.93 (d), 106.09 (d), 100.47 (t), 48.32 (t), 43.80 (t), 29.18 (t).
IR (CCl4): 3321, 3039, 3012 cm-1. LRMS (GC-MS) for C10H11
-
NO2 (M+): Calcd 177.22, found 177.05.
(S )-N′-[1-(Me t h oxym e t h yl)-2-m e t h ylp r op yl]-N ,N -d i-
m eth ylm eth a n im id a m id e (17). To a solution of (S)-valinol
(5.10 g, 49.4 mmol) in benzene (5.0 mL) at rt was added N,N-
dimethylformamide dimethylacetal (6.70 mL, 6.01 g, 50.4
mmol). After 12 h, the volatile materials were removed in
vacuo, and the residue was used in the next reaction without
further purification. To a slurry of KH (35%, 5.70 g, 49.7
mmol) and MeI (3.50 mL, 7.98 g, 56.2 mmol) in THF (25.0 mL)