1030 J. Am. Chem. Soc., Vol. 118, No. 5, 1996
Peat and Buchwald
(15 mL). The organic layer was washed with water (10 mL) and brine
(10 mL), dried over MgSO4, and filtered, and the solvents were removed
via rotary evaporation. The product was purified by flash chromatog-
raphy (2:6:2 hexane/ethyl acetate/NEt3) to give 0.28 g (82%) of a white
solid: mp 208-210.5 °C; 1H NMR (CDCl3, 300 MHz) δ 8.18 (d, J )
8.5 Hz, 1H), 7.49 (s, 1H), 6.90 (d, J ) 8.8 Hz, 1H), 4.45 (q, J ) 7.1
Hz, 2H), 3.92 (s, 3H), 3.17 (t, J ) 7.1 Hz, 2H), 2.96 (t, J ) 7.1 Hz,
2H), 2.49 (s, 3H), 1.45 (t, J ) 7.1 Hz, 3H), 1.17 (br s, 1H); 13C NMR
(CDCl3, 75 MHz) δ 154.2, 150.1, 132.3, 131.7, 125.7, 120.2, 115.6,
108.8, 77.2, 63.1, 57.5, 52.4, 36.4, 26.4, 14.3; IR (KBr, cm-1) 3239,
2934, 2784, 1733, 1411, 1252, 1128. Anal. Calcd for C15H19N2O3I:
C, 44.79; H, 4.76. Found: C, 44.69; H, 4.91.
5. Pd(PPh3)4 (92 mg, 0.08 mmol) was added to a mixture of 4 (0.32
g, 0.80 mmol), NEt3 (4 mL), and K2CO3 (0.33 g, 2.4 mmol) in toluene
(10 mL). The yellow mixture was heated to 200 °C for 15 h, cooled
to RT, and poured into a separatory funnel containing Et2O (15 mL)
and water (15 mL). The organic layer was washed with water (10
mL) and brine (10 mL), dried over MgSO4, and filtered, and the solvents
were removed using a rotary evaporator. The product was purified by
flash chromatography (4:1 hexane/ethyl acetate) to give 0.18 g (82%)
of a white powder: mp 71.1-72.8 °C; 1H NMR (CDCl3, 300 MHz) δ
7.42 (br s, 1H), 7.16 (s, 1H), 6.90 (d, J ) 8.9 Hz, 1H), 4.45 (q, J ) 7.5
Hz, 2H), 3.87 (s, 3H), 3.27 (t, J ) 6.6 Hz, 2H), 3.09 (s, 3H), 2.85 (t,
J ) 6.5 Hz, 2H), 1.44 (t, J ) 7.5 Hz, 3H); 13C NMR (CDCl3, 75 MHz)
δ 151.5, 144.0, 131.2, 129.4, 123.3, 117.4, 116.0, 113.0, 107.1, 62.7,
57.6, 52.7, 41.1, 20.0, 14.4; IR (CDCl3, cm-1) 3129, 2951, 1726, 1408,
1258, 1080. Anal. Calcd for C15H18N2O3: C, 65.68; H, 6.61.
Found: C, 65.75; H, 6.56.
containing Et2O (75 mL) and water (75 mL). The organic layer was
washed with water (2 × 50 mL) and brine (50 mL), dried over MgSO4,
and filtered, and the solvents were removed using a rotary evaporator
to give 2.45 g (94%) of a pale yellow oil: 1H NMR (CDCl3, 300 MHz)
δ 7.04 (s, 1H), 6.70 (s, 1H), 5.82 (m, 1H), 5.02 (m, 2H), 3.86 (s, 3H),
3.84 (s, 3H), 2.99 (t, J ) 7.8 Hz, 2H), 2.72 (s, 3H), 2.27 (q, J ) 7.8
Hz, 2H); 13C NMR (CDCl3, 75 MHz) δ 148.7, 144.9, 144.2, 136.3,
116.4, 115.8, 110.9, 106.5, 56.4, 56.2, 42.1, 32.1; IR (film, cm-1) 3075,
2935, 2839, 1504, 1213, 1034; HRMS (EI) for C13H18N1O2Br, calcd
299.05209, found 299.05272.
11. A solution of 1.7 M tBuLi (1.56 mL, 2.66 mmol) was added
dropwise to a Schlenk flask containing 9 (0.4 g, 1.33 mmol) and Cp2-
Zr(Me)Cl (0.36 g, 1.33 mmol) in THF (7 mL) at -78 °C. The solution
was stirred at -78 °C for 3 h and then warmed to RT. After 10 h, the
THF was removed in Vacuo to give an orange foam, which was
dissolved in CH2Cl2 (7 mL). The solution was cooled to 0 °C, and a
solution of iodine (1 g, 3.99 mmol) in THF (1 mL) and CH2Cl2 (7
mL) was quickly added. The purple solution was stirred at 0 °C for 3
h and then warmed to RT. After 3 h, the solution was poured into a
separatory funnel containing Et2O (25 mL) and saturated Na2SO3
solution (25 mL). The organic layer was dried over MgSO4 and filtered,
and the solvents were removed using a rotary evaporator to give an
orange oil. Note: the diiodide compound should not be heated since
it is thermally unstable. The oil was dissolved in THF (1 mL) and
cooled to 0 °C, and benzylamine (15 mL) was added. The solution
was allowed to warm to RT overnight, and then the excess benzyl amine
was removed via Kugelrohr distillation. Flash chromatography (2:1
hexane/ethyl acetate with 5% NEt3) of the remaining residue gave 0.47
g (78%) of an orange oil: 1H NMR (CDCl3, 300 MHz) δ 7.33-7.19
(m, 5H), 6.12 (s, 1H), 3.87 (d, J ) 13.8 Hz, 1H), 3.79 (s, 3H), 3.77 (d,
J ) 13.8 Hz, 1H), 3.69 (s, 3H), 3.20 (dt, J ) 4.0, 11.7 Hz, 1H), 3.10-
3.00 (m, 2H), 2.85 (s, 3H), 2.82 (dd, J ) 2.9, 9.3 Hz, 1H), 2.44 (dd,
J ) 10.6, 13.2 Hz, 1H), 2.19 (m, 1H), 1.79 (m, 1H), 1.39 (br s, 1H);
13C NMR (CDCl3, 75 MHz) δ 151.3, 143.5, 140.8, 139.3, 128.3, 128.0,
126.8, 117.9, 101.7, 96.8, 60.4, 56.0, 53.8, 51.8, 46.4, 41.2, 39.1, 23.2;
IR (film cm-1) 3332, 2926, 1592, 1494, 1262, 1018; HRMS (EI) for
C20H25N2O2I, calcd 452.09608, found 452.09573.
Dehydrobufotenine (1).15 A solution of 1 M BBr3 in CH2Cl2 (1
mL, 1 mmol) was added dropwise to a flask containing 5 (46 mg, 0.17
mmol) in CH2Cl2 (10 mL) at -78 °C. The solution was warmed to
RT overnight, and then the solvent was removed in Vacuo. CH2Cl2
(10 mL) and KHCO3 (0.14 g, 1.0 mmol) were added, and then the
mixture was cooled to 0 °C and MeOH (5 mL) was added dropwise.
After 0.5 h at 0 °C, the mixture was warmed to RT and stirred for 1 h.
The solvent was removed in Vacuo, and the residue was dissolved in
MeOH (5 mL). Methyl iodide (16 µL, 0.26 mmol) was added, and
the mixture was stirred at RT until TLC (10% MeOH/MeCN) showed
no remaining starting material. The solvent was removed using a rotary
evaporator, and the residue was extracted with CH2Cl2. The organic
phase was concentrated to give a gray solid. Slow recrystallization
from MeOH gave 28 mg (50%) of a gray-white solid: mp 241.0-
12. A mixture of 11 (0.4 g, 0.88 mmol), Pd2(dba)3 (20 mg, 0.022
mmol), P(o-tolyl)3 (28 mg, 0.088 mmol), and NaOtBu (0.34 g, 3.52
mmol) in toluene (5 mL) was heated to 80 °C for 20 h, cooled to RT,
and poured into a separatory funnel containing Et2O (20 mL) and water
(20 mL). The organic layer was washed with water (15 mL) and brine
(15 mL), dried over MgSO4, and filtered, and the solvents were removed
using a rotary evaporator. The product was purified by flash chroma-
tography (10:1 hexane/ethyl acetate) to give 0.21 g (72%) of a yellow
oil: 1H NMR (CDCl3, 300 MHz) δ 7.44-7.26 (m, 5H), 5.75 (s, 1H),
5.14 (d, J ) 14.5 Hz, 1H), 4.01 (d, J ) 14.4 Hz, 1H), 3.87 (s, 3H),
3.73 (s, 3H), 3.43 (t, J ) 8.1 Hz, 1H), 3.22-3.14 (m, 3H), 2.90 (s,
1
243.8 °C; H NMR (CD3OD, 300 MHz) δ 7.09 (d, J ) 8.3 Hz, 1H),
6.90 (s, 1H), 6.62 (d, J ) 8.3 Hz, 1H), 3.9 (t, J ) 5.4 Hz, 2H), 3.7 (s,
6H), 3.24 (t, J ) 5.4 Hz, 2H); 13C NMR (CDCl3, 75 MHz) δ 161.4,
134.2, 130.4, 122.6, 120.0, 114.8, 104.1, 102.8, 69.5, 53.7, 20.2. Anal.
Calcd for C12H15N2OI: C, 43.65; H, 4.58. Found: C, 43.97; H, 4.46.
2-Bromo-4,5-dimethoxyaniline (7).27 Bu4NBr3 (36 g, 75 mmol)
was added to a solution of 4-aminoveratrole (10 g, 65 mmol) in CH2-
Cl2 (265 mL) and MeOH (130 mL). After 20 min at RT, the solution
was poured into a separatory funnel containing Et2O (300 mL) and
saturated Na2SO3 solution (300 mL). The organic layer was washed
with water (200 mL), dried over MgSO4, and filtered, and the solvents
were removed using a rotary evaporator. The product was purified by
flash chromatography (10:1 and then 4:1 hexane/ethyl acetate) to give
10.7 g (67%) of a purple oil: 1H NMR (CDCl3, 300 MHz) δ 6.92 (s,
3H), 6.38 (s, 1H), 3.83-3.76 (br s, 2H), 3.81 (s, 3H), 3.78 (s, 3H).
8. A mixture of 7 (9.9 g, 42.7 mmol), sodium iodide (19.4 g, 129
mmol), K2CO3 (17.8 g, 129 mmol), and 4-bromo-1-butene (6.5 mL,
64 mmol) in DMF (150 mL) was heated to 100 °C for 10 h, cooled to
RT, and poured into a separatory funnel containing Et2O (200 mL)
and water (200 mL). The organic layer was washed with water (2 ×
100 mL) and brine (100 mL), dried over MgSO4, and filtered, and the
solvents were removed using a rotary evaporator. The product was
purified by flash chromatography (10:1 and then 4:1 hexane/ethyl
acetate) to give 9.0 g (74%) of a colorless oil: 1H NMR (CDCl3, 300
MHz) δ 6.97 (s, 1H), 6.28 (s, 1H), 5.82 (m, 1H), 5.17 (m, 2H), 4.00
(br s, 1H), 3.86 (s, 3H), 3.79 (s, 3H), 3.20 (q, J ) 6.1 Hz, 2H), 2.42
(q, J ) 5.9 Hz, 2H); 13C NMR (CDCl3, 75 MHz) δ 149.2, 140.6, 139.4,
3H), 2.68 (dd, J ) 8.5, 11.9 Hz, 1H), 2.07 (m, 1H), 1.70 (m, 1H); 13
C
NMR (CDCl3, 75 MHz) δ 154.7, 142.9, 139.4, 139.3, 128.4, 128.2,
127.2, 126.8, 108.4, 87.3, 62.2, 61.1, 56.3, 54.5, 51.0, 37.8, 35.4, 27.0;
IR (film, cm-1) 2934, 2822, 1622, 1504, 1256, 1101; HRMS (EI) for
C20H24N2O2, calcd 324.18378, found 324.18341.
16a,19b
13.
A mixture of 12 (0.12 g, 0.37 mmol), 5 mol % Pd/C by
weight (79 mg, 0.037 mmol), and ammonium formate (0.23 g, 3.7
mmol) in MeOH (6 mL) was heated to reflux for 17 h, cooled to RT,
and filtered through Celite. The MeOH was removed via rotary
evaporation, and the residue was dissolved in CH2Cl2 (10 mL). The
organic phase was washed with water (5 mL), dried over MgSO4, and
filtered, and the solvents were removed using a rotary evaporator. The
product was purified by flash chromatography (4:1 hexane/ethyl acetate)
to give 69 mg (80%) of an amorphous solid: 1H NMR (CDCl3, 300
MHz) δ 7.97 (br s, 1H), 6.64 (s, 1H), 6.01 (s, 1H), 3.94 (s, 3H), 3.92
(s, 3H), 3.26 (t, J ) 5.7 Hz, 2H), 3.04 (t, J ) 5.7 Hz, 2H), 2.94 (s,
3H); 13C NMR (CDCl3, 75 MHz) δ 149.2, 139.2, 127.8, 114.7, 114.4,
111.0, 89.3, 61.0, 58.2, 52.8, 38.2, 23.4; IR (film, cm-1) 3345, 2932,
1621, 1520.
134.9, 116.9, 116.4, 98.4, 96.9, 56.5, 55.6, 43.2, 33.1; IR (film, cm-1
)
3395, 2931, 1515, 1211; HRMS (EI) for C12H16N1O2Br, calcd
285.03644, found 285.03667.
Acknowledgment. We would like to thank the National
Institutes of Health for funding. Additional support from Dow
Chemical and Pfizer is gratefully acknowledged.
9. A mixture of 8 (2.5 g, 8.74 mmol), K2CO3 (3.62 g, 26.2 mmol),
and methyl iodide (1.62 mL, 26.2 mmol) in DMF (30 mL) was heated
to 100 °C for 2 h, cooled to RT, and poured into a separatory funnel
(27) Stogryn, E. L. J. Med. Chem. 1969, 12, 185.
JA953080T