Kinderman et al.
to 0:1) to yield the product as a yellowish oil. Yield 68 mg (0.249
mmol, 98%). Rf 0.13 (EtOAc). IR (CHCl3) ν 1121, 1229, 1254,
1435, 1464, 1518, 1633, 2938 cm-1. 1H NMR (500 MHz) δ 6.65
(s, 1H), 6.63 (s, 1H), 5.78-5.69 (m, 3H), 4.06-4.02 (m, 1H),
3.88 (s, 3H), 3.87 (s, 3H), 3.52-3.47 (m, 1H), 3.40-3.37 (m,
1H), 2.76-2.74 (m, 2H), 2.54-2.50 (m, 3H). 13C NMR (125
MHz) δ 173.6, 147.9, 147.8, 133.0, 131.5, 128.0, 127.3, 110.9,
109.4, 56.0, 55.8, 52.4, 38.3, 33.4, 28.5, 25.4. HRMS (FAB) calcd
for C16H20NO3 (MH+) 274.1443, found 274.1443.
6-Chloro-2-tert-butyloxycarbonyl-1-vinyl-2,3,4,9-tet-
rahydro-1H-â-carboline (70). To a solution of 6-chloro-1-
vinyl-2,3,4,9-tetrahydro-1H-â-carboline (69) (0.218 g, 0.937
mmol) in dichloromethane (20 mL) was added Boc2O (0.205 g,
0.937 mmol, 1 equiv). The solution was refluxed for 6 h, then
H2O (50 mL) was added, followed by layer separation. The
aqueous layer was extracted with EtOAc (30 mL) and the
combined organic layers were washed with 1% aqueous HCl
(30 mL), saturated aqueous NaHCO3 (30 mL), and brine (30
mL) and concentrated in vacuo. Column chromatography
(pentane/ethyl acetate 4:1 to 2:1) afforded the product as an
off-white solid. Yield 0.312 g (0.937 mmol, 100%). Rf 0.42
(pentane/ethyl acetate 2:1). IR (CHCl3) ν 1167, 1413, 1679,
6-Chloro-2-(4-nitrobenzenesulfonyl)-1-vinyl-2,3,4,9-tet-
rahydro-1H-â-carboline (66). To a solution of N-[2-(5-chloro-
1H-indol-3-yl)ethyl]-4-nitrobenzenesulfonamide (65, 2.99 g,
7.87 mmol) in acetonitrile (40 mL) was added Et3N (1.64 mL,
11.8 mmol), Pd(OAc)2 (88 mg, 0.39 mmol), dppp (160 mg, 0.39
mmol), and benzyl propadienyl ether (1.14 g, 8.66 mmol). After
being stirred for 6 h at room temperature the solution was
concentrated and purified by column chromatography with
silica gel with some Et3N in the eluent. Yield 3.40 g (6.50
mmol, 83%). Rf 0.49 (pentane/ethyl acetate 1:1). 1H NMR (400
MHz) δ 8.22 (d, J ) 8.8 Hz, 2H), 8.12 (br s, NH), 7.97 (d, J )
8.8 Hz, 2H), 7.55 (d, J ) 1.8 Hz, 1H), 7.38-7.30 (m, 5H), 7.23
(d, J ) 8.6 Hz, 1H), 7.12 (dd, J ) 2.0, 8.6 Hz, 1H), 7.00 (d,
J ) 2.2 Hz, 1H), 5.75 (d, J ) 2.7 Hz, 1H), 5.60-5.55 (m, 2H),
5.40-5.37 (m, 1H), 4.73 (d, J ) 13.1 Hz, 1H), 4.65 (d, J ) 11.9
Hz, 1H), 3.51-3.43 (m, 1H), 3.39-3.32 (m, 1H), 3.15-3.11 (m,
2H). 13C NMR (100 MHz) δ 145.8, 140.6, 136.8, 134.4, 132.9,
128.4, 128.3, 128.1, 127.9, 127.8, 127.5, 126.8, 125.0, 124.1,
124.0, 122.2, 119.9, 118.1, 112.2, 112.1, 86.6, 69.6, 44.5, 26.8.
To an ice-cold solution of the crude N,O-acetal (3.19 g, 6.06
mmol) in CH2Cl2 (100 mL) was added Sn(OTf)2 (50 mg, 0.12
mmol). The mixture was stirred for 1-2 h at 0 °C and
quenched with a few drops of Et3N. The solution was concen-
trated in vacuo and purified by column chromatography as
indicated. The crude reaction mixture was diluted with EtOAc
and washed with H2O (30 mL) and brine (30 mL), dried over
Na2SO4, and concentrated. Column chromatography (pentane/
ethyl acetate 2:1) afforded the product as a yellow solid. Yield
2.37 g (5.7 mmol, 94%). Rf 0.26 (pentane/ethyl acetate 2:1).
1
2981, 3466 cm-1. H NMR (500 MHz) δ 7.47 (s, 1H), 7.24 (d,
J ) 8.5 Hz, 1H), 7.13 (dd, J ) 2.0, 8.8 Hz, 1H), 6.04-5.97 (m,
1H), 5.90-5.50 (br m, 1H), 5.27 (d, J ) 10.0 Hz, 1H), 5.18 (br
d, J ) 15.6 Hz, 1H), 4.60-4.20 (br m, 1H), 3.13 (br s, 1H),
2.85-2.79 (m, 1H), 2.72-2.67 (m, 1H), 1.54 (s, 9H). 13C NMR
(125 MHz) δ 154.7, 135.0, 134.5, 133.1, 129.0, 128.0, 127.5,
125.2, 122.0, 117.8, 117.5, 111.8, 80.31, 29.7, 28.5, 21.3. HRMS
(FAB) calcd for C18H22N2O2Cl (MH+) 333.1370, found 333.1388.
6-Chloro-1-(2-methoxycarbonylvinyl)-1,3,4,9-tetrahy-
dro-â-carboline-2-carboxylic Acid tert-Butyl Ester (71).
To a degassed solution of 70 (0.365 g, 1.1 mmol) in toluene
(20 mL) was added methyl acrylate (1.0 mL, 11 mmol, 10
equiv) and Hoveyda-Grubbs catalyst (15 mg, 0.022 mmol, 2
mol %). The solution was heated at 60 °C for 48 h. After
concentration in vacuo, column chromatography (pentane/
diethyl ether 2:1 to 1:1) afforded the product as a colorless oil.
Yield 0.353 g (0.902 mmol, 82%). Rf 0.13 (pentane/diethyl ether
1:1). IR (CHCl3) ν 1166, 1284, 1414, 1678, 2981, 3327, 3463
cm-1. 1H NMR (400 MHz) δ 9.27 and 8.72 (br s, NH), 7.42 (s,
1H), 7.20 (br d, J ) 8.1 Hz, 1H), 7.08 (d, J ) 8.6 Hz, 1H), 6.99
(br d, J ) 12.8 Hz, 1H), 6.00-5.73 (m, 2H), 4.45 and 4.32 (br
s, 1H), 3.75 and 3.67 (br s, 3H), 3.09-3.01 (m, 1H), 2.84-2.76
(m, 1H), 2.66-2.63 (m, 1H), 1.56 and 1.47 (br s, 9H). HRMS
(FAB) calcd for C20H24N2O4Cl (MH+) 391.1425, found 391.1420.
6-Chloro-1-(2-methoxycarbonylethyl)-1,3,4,9-tetrahy-
dro-â-carboline-2-carboxylic Acid tert-Butyl Ester (72).
The olefin 71 (0.29 g, 0.742 mmol) was dissolved in dry
methanol (15 mL) together with a catalytic amount of PtO2.
The stirred solution was exposed to 1 atm of H2 pressure for
1 h. Filtration of the suspension over Hyflo and concentration
in vacuo afforded the product as a yellowish foam. Yield 0.29
g (0.74 mmol, 99%). Rf 0.55 (pentane/ethyl acetate 1:1). IR
(CHCl3) ν 1167, 1232, 1367, 1417, 1671, 1725, 2932, 2980,
Mp 225.6-226.0 °C. IR (CHCl3) ν 1030, 1248, 1708, 3387 cm-1
.
1H NMR (400 MHz, CDCl3 + acetone-d6) δ 9.52 (br s, NH),
7.98 (d, J ) 9.0 Hz, 2H), 7.76 (d, J ) 8.8 Hz, 2H), 7.04 (d, J )
2.0 Hz, 1H), 6.99 (d, J ) 8.5 Hz, 1H), 6.79 (dd, J ) 2.0, 8.5 Hz,
1H), 5.73-5.67 (m, 1H), 5.46 (d, J ) 5.9 Hz, 1H), 5.01 (d, J )
10.0 Hz, 1H), 4.95 (d, J ) 17.1 Hz, 1H), 3.93-3.89 (m, 1H),
3.17-3.11 (m, 1H), 2.39-2.35 (m, 2H). 13C NMR (125 MHz,
CDCl3 + acetone-d6) δ 149.3, 146.2, 134.2, 134.0, 131.2, 127.6,
127.0, 124.3, 123.6, 121.6, 118.2, 117.0, 111.7, 107.1, 54.7, 39.4,
20.1. HRMS (FAB) calcd for C19H17N3O4SCl (MH+) 418.0628,
found 418.0628. Anal. Calcd for C19H16N3O4SCl: C, 54.61; H,
3.86; N, 10.06. Found: C, 54.74; H, 3.92; N, 9.94.
1
3327, 3463 cm-1. H NMR (400 MHz) δ 9.17 and 8.77 (br s,
NH), 7.44 (s, 1H), 7.22 (d, J ) 8.5 Hz, 1H), 7.10 (d, J ) 8.5
Hz, 1H), 5.41 and 5.30 (br s, 1H), 4.50 and 4.31 (br s, 1H),
3.76 and 3.65 (br s, 3H), 3.18-3.08 (m, 1H), 2.83-2.79 (m, 1H),
2.65 (d, J ) 15.4 Hz, 1H), 2.51-2.46 (m, 1H), 2.25-2.19 (m,
1H), 2.13-2.05 (m, 1H), 1.55 and 1.51 (br s, 9H). 13C NMR
(125 MHz) both conformers: δ 173.9, 155.4, 154.6, 135.6, 135.2,
134.4, 127.8, 124.8, 121.7, 117.5, 111.9, 108.5, 107.9, 80.2, 51.6,
50.7, 50.2, 38.6, 37.3, 30.6, 29.6, 29.4, 28.3, 21.2, 20.9. HRMS
(FAB) calcd for C20H26N2O4Cl (MH+) 393.1581, found 393.1578.
6-Chloro-1-vinyl-2,3,4,9-tetrahydro-1H-â-carboline (69).
To an ice-cold solution of sulfonamide 66 (0.40 g, 0.96 mmol)
in MeCN (10 mL) was added potassium thiophenolate (1.38
g, 1.48 mmol) and the mixture was stirred at room tempera-
ture for 48 h. Water (10 mL) was added and the product was
extracted with EtOAc (3 × 20 mL). The organic layers were
washed with brine, dried over Na2SO4, and concentrated.
Column chromatography (CH2Cl2/MeOH/25% NH3 90:10:1/2)
afforded the product as an off-white solid. Yield 177 mg (0.76
mmol, 80%). Rf 0.12 (CH2Cl2/MeOH/25% NH3 90:10:1/2). IR
10-Chloro-6-oxo-1,2,3a,4,5,6-hexahydroindolo[3,2,1-de]-
[1,5]naphthyridine-3-carboxylic Acid tert-Butyl Ester
(73). To an ice-cold solution of the ester 72 (0.213 g, 0.542
mmol) in dry toluene (10 mL) was added NaHMDS (1 M in
toluene, 1.88 mL, 1.88 mmol) and stirring was continued for
2 h at room temperature. The solution was cooled to 0 °C and
ice-cold saturated aqueous NaHCO3 (15 mL) was added. The
product was extracted with CH2Cl2 (2 × 15 mL) after layer
separation. The organic layers were washed with brine (15
mL), dried over Na2SO4, and concentrated. Column chroma-
tography (pentane/ethyl acetate 3:1 to 1:1) afforded the product
as a colorless oil. Yield 76 mg (0.211 mmol, 39%). Rf 0.49
(pentane/ethyl acetate 1:1). IR (CHCl3) ν 1216, 1402, 1692,
1
(CHCl3) ν 1064, 1294, 1441, 2205, 2360, 2918, 3466 cm-1. H
NMR (400 MHz) δ 7.88 (br s, NH), 7.45 (d, J ) 1.9 Hz, 1H),
7.18 (d, J ) 8.6 Hz, 1H), 7.08 (dd, J ) 2.0, 8.6 Hz, 1H), 6.00-
5.92 (m, 1H), 5.37 (d, J ) 17.1 Hz, 1H), 5.31 (d, J ) 10.0 Hz,
1H), 4.58 (d, J ) 7.8 Hz, 1H), 3.36-3.31 (m, 1H), 3.11-3.05
(m, 1H), 2.80-2.65 (m, 2H), 1.91 (br s, NH). 13C NMR (100
MHz) δ 137.9, 134.9, 133.9, 128.6, 124.9, 121.6, 118.2, 117.6,
111.5, 108.8, 56.4, 42.0, 22.0. HRMS (FAB) calcd for C13H14N2-
Cl (MH+) 233.0846, found 233.0835. Anal. Calcd for C13H13N2-
Cl: C, 67.10; H, 5.63; N, 12.04. Found: C, 67.02; H, 5.54; N,
12.15.
3020 cm-1 1H NMR (500 MHz) δ 8.31 (d, J ) 8.5 Hz, 1H),
.
7.44 (s, 1H), 7.30 (d, J ) 8.8 Hz, 1H), 4.98 (d, J ) 9.5 Hz, 1H),
4.48 (d, J ) 12.4 Hz, 1H), 2.96-2.88 and 2.73-2.68 (m, 5H),
5526 J. Org. Chem., Vol. 70, No. 14, 2005