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to a solution of N,N-diethyl-4-methylbenzenesulfonamide (0.800 g,
3.50 mmol) in tetrahydrofuran (10 mL) under argon atmosphere. The
reaction mixture was stirred for 1 h at −78 °C, and then a solution of
di-tert-butyl azodicarboxylate (0.97 g, 4.20 mmol) in tetrahydrofuran
(10 mL) was added dropwise. The mixture was stirred at −78 °C for
1 h and then at 0 °C for 1 h. Water (10 mL) was added followed by
ethyl acetate (10 mL). The phases were separated, and the organic
layer was dried with MgSO4, filtered, and evaporated in vacuo.
Column chromatography of the residue eluting with ethyl acetate and
light petroleum (1:19) gave the title compound as a colorless solid
(1.20 g, 75%): mp 139−140 °C; found M + Na+, 480.2133,
C21H35N3O6S + Na+ requires 480.2139; νmax (CHCl3)/cm−1 3015,
2982, 2936, 1731, 1716, 1601, 1477, 1369, 1325, 1241, 1154; δH (400
MHz; CDCl3) 7.82 (1H, d, J 8.0), 7.63 (1H, s), 7.58 (1H, br s), 7.25
(1H, d, J 8.0), 3.38 (2H, q, J 7.1), 3.14 (2H, q, J 7.1), 2.42 (3H, s),
1.52 (9H, s), 1.46 (9H, s), 1.11 (6H, t, J 7.1); δC (100 MHz; CDCl3)
154.5, 154.2, 145.0, 139.2, 134.7, 133.1 (CH), 130.3 (CH), 129.4
(CH), 82.0, 81.0, 41.6 (CH2), 28.2 (Me), 28.1 (Me), 21.3 (Me), 14.2
(Me); m/z (ESI) 480 (M + Na+, 100). Anal. Calcd for C21H35N3O6S:
C, 55.12; H, 7.71; H, 9.18. Found: C, 55.05; H, 7.71; N, 9.13.
6-(4-Toluenesulfonyloxy)-1,2,3,4-tetrahydrocarbazole (3c). Hy-
drochloric acid (35%; 2 mL) was added to a suspension of di-tert-
butyl 1-(4-(tosyloxy)phenyl)hydrazine-1,2-dicarboxylate (2c) (0.239 g,
0.5 mmol), cyclohexanone (0.098 g, 1.0 mmol), and ethanol (2 mL),
and the mixture was stirred at 70 °C for 2 h, cooled to room
temperature, diluted with water (20 mL), and extracted with ethyl
acetate (3 × 10 mL). The combined organic phases were dried
(MgSO4), filtered, and concentrated. Column chromatography eluting
with ethyl acetate and light petroleum (1:6) gave the title compound as
a pale yellow solid (0.154 g, 90%): mp 112−114 °C; found M + H+,
342.1166, C19H20NO3S requires 342.1164; νmax (CHCl3)/cm−1 3605,
3011, 2941, 1600, 1477, 1369; δH (400 MHz; CDCl3) 7.80 (1H, br s),
7.72 (2H, d, J 7.8), 7.29 (2H, d, J 7.8), 7.10−7.08 (2H, m), 6.65 (1H,
dd, J 8.8, 2.4), 2.71 (2H, t, J 6.0), 2.60 (2H, t, J 5.8), 2.07 (3H, s),
1.92−1.84 (4H, m); δC (100 MHz; CDCl3) 144.9, 143.1, 136.3, 134.0,
132.7, 129.6 (CH), 128.6 (CH), 128.0, 115.2 (CH), 111.3 (CH),
110.7 (CH), 110.6, 23.2 (CH2), 23.1 (CH2), 23.0 (CH2), 21.7 (Me),
20.7 (CH2); m/z (ESI) 364 (M + Na+, 100%), 342 (M + H+, 63).
Methyl 5,6,7,8-Tetrahydrocarbazole-3-carboxylate (3d). A sus-
pension of di-tert-butyl 1-(4-(methoxycarbonyl)phenyl)hydrazine-1,2-
dicarboxylate (2d) (0.183 g, 0.5 mmol), cyclohexanone (0.098 g, 1.0
mmol), and trifluoroacetic acid (2 mL) was stirred at 70 °C for 4 h,
cooled to room temperature, diluted with saturated sodium hydrogen
solution (30 mL), and extracted with ethyl acetate (3 × 20 mL). The
combined organic phases were dried (MgSO4), filtered, and
concentrated. Column chromatography eluting with ethyl acetate
and light petroleum (1:7) gave the title compound as a colorless solid
(0.102 g, 89%): mp 153−155 °C (lit.64 mp 155−157 °C); found
M + H+, 230.1174. C14H16NO2 requires 230.1181; νmax (CHCl3)/cm−1
3468, 3011, 2946, 2846, 1703, 1312, 1243; δH (400 MHz; CDCl3)
8.26 (1H, s), 8.03 (1H, br s), 7.86 (1H, dd, J 8.6, 1.6), 7.29 (1H, d,
J 8.6), 3.96 (3H, s), 2.77−2.75 (4H, m), 1.97−1.67 (4H, m); δC (100
MHz; CDCl3) 168.5, 138.4, 135.6, 127.5, 122.6 (CH), 121.0, 120.7
(CH), 111.5, 110.0 (CH), 51.8 (Me), 23.2 (CH2), 23.1 (CH2), 23.0
(CH2), 20.8 (CH2); m/z (ESI) 481 (2M + Na+, 100), 252 (M + Na+,
33), 230 (M + H+, 25).
Synthesis of Indoles. Ethyl 7-Bromo-3-methylindole-2-car-
boxylate (3a). Hydrochloric acid (35%; 5 mL) was added to a
suspension of di-tert-butyl 1-(2-bromophenyl)hydrazine-1,2-dicarbox-
ylate (2a) (0.386 g, 1.0 mmol), 2-ketobutyric acid (0.102 g, 1.0
mmol), and ethanol (5 mL), and the mixture was stirred at 70 °C for
16 h, cooled to room temperature, diluted with water (50 mL), and
extracted with ethyl acetate (3 × 20 mL). The combined organic
phases were dried (MgSO4), filtered, and concentrated. Column
chromatography eluting with ethyl acetate and light petroleum (1:50)
gave the title compound as a colorless solid (0.196 g, 70%): mp 81−
83 °C; found M + Na+, 303.9965, C12H1279BrNaNO2 requires 303.9949;
νmax (CHCl3)/cm−1 3452, 2985, 2938, 1700, 1311, 1242; δH (400
MHz; CDCl3) 8.78 (1H, br s), 7.62 (1H, dd, J 8.0, 0.7), 7.49 (1H, dd,
J 7.5, 0.7), 7.04 (1H, dd, J 8.0, 7.5), 4.47 (2H, q, J 7.2), 2.62 (3H, s),
1.47 (3H, t, J 7.2); δC (100 MHz; CDCl3) 162.2, 134.6, 129.6, 127.7
(CH), 124.1, 121.0, 120.9 (CH), 120.0 (CH), 105.0, 61.0 (CH2), 14.5
(Me), 10.2 (Me); m/z (ESI) 304 (M + Na+, 100%), 305 (M + Na+,
98).
3-Methyl-5-(morpholinosulfonyl)indole-2-carboxylic Acid (3e).
Hydrochloric acid (35%; 2 mL) was added to a suspension of di-tert-
butyl 1-(4-(morpholinosulfonyl)phenyl)hydrazine-1,2-dicarboxylate
2e (0.229 g, 0.5 mmol), 2-ketobutyric acid (0.051 g, 0.5 mmol), and
acetic acid (2 mL), and the mixture was stirred at 70 °C for 3 h, cooled
to room temperature and diluted with water (25 mL). The resulting
precipitate was collected by filtration and dried in vacuo to give the
title compound as a gray solid (0.134 g, 83%): mp >250 °C; found M +
H+, 325.0862, C14H17N2O5S requires 325.0858; νmax (CHCl3)/cm−1
3320, 2987, 2845, 1683, 1363; δH (400 MHz; CDCl3) 8.05 (1H, s),
7.61−7.55 (2H, m), 3.62 (4H, t, J 4.6), 2.85 (4H, t, J 4.6), 2.59 (3H, s);
δC (100 MHz; CDCl3) 163.5, 138.2, 127.7, 127.0, 125.5, 123.6 (CH),
122.1 (CH), 119.7, 113.5 (CH), 65.8 (CH2), 46.5 (CH2), 10.1 (Me);
m/z (ESI) 347 (M + Na+, 100), 325 (56).
Ethyl 5-Fluoro-3-methylindole-2-carboxylate (3b). Hydrochloric
acid (35%; 5 mL) was added to a suspension of di-tert-butyl 1-(4-
fluorophenyl)hydrazine-1,2-dicarboxylate (2b) (0.386 g, 1.0 mmol), 2-
ketobutyric acid (0.102 g, 1.0 mmol), and ethanol (5 mL), and the
mixture was stirred at 70 °C for 16 h, cooled to room temperature,
diluted with water (50 mL), and extracted with ethyl acetate (3 × 20
mL). The combined organic phases were dried (MgSO4), filtered, and
concentrated. Column chromatography eluting with ethyl acetate and
light petroleum (1:14) gave the title compound as a colorless solid
(0.146 g, 66%): mp 121−123 °C; found M + Na+, 244.0745,
C12H12FNaNO2 requires 244.0750; νmax (CHCl3)/cm−1 3463, 2985,
2938, 1695, 1456, 1242; δH (400 MHz; DMSO-d6) 7.43−7.39 (2H,
m), 7.12 (1H, ddd, J 9.4, 8.9, 2.4), 4.34 (2H, q, J 7.2), 2.51 (3H, s),
1.34 (3H, t, J 7.2); δC (100 MHz; DMSO-d6) 162.2, 127.3 (d, J 233,
CF), 133.4, 128.2 (d, J 9.6, C), 125.3, 118.7 (d, J 5.8, C), 114.2 (d,
J 24, CH), 114.1 (d, J 12, CH), 105.0 (d, J 23, CH), 60.7 (CH2), 14.7
(Me), 10.2 (Me); m/z (ESI) 244 (M + Na+, 100%).
6-Chloro-2,3-dimethylindole (3f). Hydrochloric acid (35%; 4 mL)
was added to a suspension of di-tert-butyl 1-(3-chlorophenyl)-
hydrazine-1,2-dicarboxylate 2f (0.342 g, 1.0 mmol), butan-2-one
(0.144 g, 2.0 mmol), and ethanol (4 mL), and the mixture was stirred
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dx.doi.org/10.1021/jo201866c|J. Org. Chem. 2012, 77, 1217−1232