10260 J. Am. Chem. Soc., Vol. 121, No. 44, 1999
Wagaw et al.
The reaction mixture was cooled to room temperature, diluted with
Et2O (5 mL), and neutralized with a saturated NaHCO3 solution. The
aqueous layer was extracted with Et2O (3 × 10 mL), and the combined
organic extracts were dried (K2CO3), filtered, and concentrated under
vacuum. Purification of the crude product by flash chromatography
afforded the analytically pure indole product.
2,5-Dimethyl-3-pentylindole 5f. Procedure D was used to convert
hydrazone 4f (387 mg, 1.35 mmol) and 2-octanone (317 µL, 2.03 mmol)
to the title product. Purification of the crude product by flash
chromatography (NEt3-deactivated silica gel, 10% EtOAc/hexanes)
afforded 5f as a yellow oil (225 mg, 77% yield). 1H NMR (300 MHz,
CDCl3): δ 7.55 (br s, 1 H), 7.26 (s, 1 H), 7.15 (d, J ) 8.1 Hz, 1 H),
6.92 (d, J ) 8.1 Hz, 1 H), 2.64 (t, J ) 7.5 Hz, 2 H), 2.44 (s, 3 H), 2.34
(s, 3 H), 1.62-1.56 (m, 2 H), 1.31 (m, 4 H), 0.88 (t, J ) 6.5 Hz, 3 H).
13C{1H} NMR (75 MHz, CDCl3): δ 133.5, 130.7, 129.0, 127.9, 122.1,
117.9, 111.9, 109.8, 31.8, 30.5, 24.1, 22.6, 21.6, 14.1, 11.6. IR (neat,
cm-1): 3041, 2926, 2856, 1459, 1305, 759. Anal. Calcd for C15H21N:
C, 83.67; H, 9.83. Found: C, 83.55; H, 10.02.
6-Chloro-1,2,3,4-tetrahydrocarbazole 5a.53 Procedure D was used
to convert hydrazone 4a (306 mg, 1.0 mmol) and cyclohexanone (160
µL, 1.5 mmol) to the title product. Purification of the crude product
by flash chromatography (10% EtOAc/hexanes) gave 5a as a white
solid (188 mg, 91% yield). Mp: 142-143 °C; lit. mp 143-144 °C.
1H NMR (300 MHz, CDCl3): δ 7.68 (s, 1 H), 7.41 (d, J ) 1.9 Hz, 1
H), 7.17 (d, J ) 8.6 Hz, 1 H), 7.05 (dd, J ) 2.0, 8.6 Hz, 1 H), 2.73-
2.64 (m, 4 H), 1.92-1.85 (m, 2 H). 13C NMR (75 MHz, CDCl3): δ
135.6, 133.9, 129.0, 124.7, 120.9, 117.3, 111.1, 110.1, 23.3, 20.9. IR
(neat, cm-1): 3405, 2941, 2845, 1579, 1467, 1436. Anal. Calcd for
C12H12NCl: C, 70.07; H, 5.88. Found: C, 70.18; H, 6.13.
(2-Methylbenzo[g]indol-3-yl)acetic Acid Ethyl Ester 5g. Procedure
D was used to convert hydrazone 4g (322 mg, 1.0 mmol) and levulinic
acid (180 µL, 1.5 mmol) to the title product. Purification of the crude
product by flash chromatography (20% EtOAc/hexanes) provided 5g
1
as a white solid (238 mg, 89% yield). Mp: 157-159 °C. H NMR
2,3,3,4,6-Pentamethyl-3H-indole 5b. Procedure D was used to
convert hydrazone 4b (300 mg, 1.0 mmol) and 3-methyl-2-butanone
(160 µL, 1.5 mmol) to the title product. Purification of the crude product
by flash chromatography (30% EtOAc/hexanes) afforded the title
(300 MHz, CDCl3): δ 8.61 (s, 1 H), 7.91 (t, J ) 7.5 Hz, 2 H), 7.66 (d,
J ) 8.6 Hz, 1 H), 7.51-7.44 (m, 2 H), 7.39-7.35 (m, 1 H), 4.15 (q,
J ) 7.1 Hz, 3 H), 3.74 (s, 3 H), 2.49 (s, 3 H), 1.24 (t, J ) 7.2 Hz, 3
H). 13C{1H} NMR (125 MHz, CDCl3): δ 172.3, 130.8, 129.9, 129.2,
128.8, 125.2, 124.1, 123.3, 121.2, 120.2, 119.1, 118.5, 106.2,60.8, 30.5,
14.2, 11.6. IR (neat, cm-1): 3343, 2990, 1704, 1429, 1399. Anal. Calcd
for C17H17NO2: C, 76.38; H, 6.41. Found: C, 76.24; H, 6.30.
2-Phenylbenzo[g]indole 5h. Procedure D was used to convert
hydrazone 4g (322 mg, 1.0 mmol) and acetophenone (170 µL, 1.5
mmol) to the title product. Purification of the crude product by flash
chromatography (5% EtOAc/hexanes) afforded 5h as a white solid (200
1
compound as a yellow oil (168 mg, 90% yield). H NMR (500 MHz,
CDCl3): δ 7.18 (s, 1 H), 6.78 (s, 1 H), 2.41 (s, 3 H), 2.35 (s, 3 H),
2.24 (s, 3 H), 1.36 (s, 6 H). 13C NMR (125 MHz, CDCl3): δ 187.8,
154.2, 139.4, 137.2, 132.1, 127.8, 118.2, 53.8, 21.1, 20.7, 17.5, 15.0.
IR (neat, cm-1): 2968, 2926, 1722, 1695, 1583. Anal. Calcd for
C13H17N: C, 82.05; H, 10.59. Found: C, 81.97; H, 10.30.
4,5-Dimethylindole-2-carboxylic Acid Ethyl Ester 5c. Hydrazone
4b (300 mg, 1.0 mmol), ethyl pyruvate (160 µL, 1.5 mmol), and
p-TsOH‚H2O (380 mg, 2.0 mmol) were dissolved in toluene (5 mL),
and the solution was heated to reflux until 4b was consumed, as
determined by GC analysis (12 h). The reaction solution was cooled
to room temperature, neutralized with a saturated NaHCO3 solution,
and extracted with EtOAc (3 × 10 mL). The combined EtOAc extracts
were dried over anhydrous K2CO3, filtered, and concentrated in vacuo
to afford the crude product as a brown oil. Purification by flash
chromatography (10% EtOAc/hexanes) afforded indole 5c as a white
solid (147 mg, 68% yield). Mp: 108 °C. 1H NMR (300 MHz, CDCl3):
δ 8.77 (s, 1 H), 7.71 (dd, J ) 1.0, 2.1 Hz, 1 H), 7.03 (s, 1 H), 6.79 (s,
1 H), 4.40 (q, J ) 7.1 Hz, 2 H), 2.52 (s, 3 H), 2.43 (s, 3 H), 1.42 (t,
J ) 7.1 Hz, 3 H). 13C{1H} (75 MHz, CDCl3): δ 162.1, 137.1, 135.7,
131.7, 126.1, 125.5, 122.8, 108.9, 107.2, 60.8, 21.9, 18.6, 14.5. IR (neat,
cm-1): 3321, 2973, 2917, 2904, 2858, 1686, 1580, 1524, 1432. Anal.
Calcd for C13H15NO2: C, 71.87; H, 6.96. Found: C, 72.13; H, 6.95.
2-Ethyl-3-methyl-6-methoxyindole 5d. Procedure D was used to
convert hydrazone 4c (302 mg, 1.0 mmol) and 3-pentanone (160 µL,
1.5 mmol) to an approximately 4:1 mixture of the 6-methoxy- and
4-methoxyindole regioisomeric products, as determined by GC and 1H
NMR analysis. Purification of the crude product by flash chromatog-
raphy (10% Et2O/hexanes) afforded isomerically pure 5d as a white
1
mg, 82% yield). Mp: 164-165 °C. H NMR (300 MHz, CDCl3): δ
9.02 (s, 1 H), 8.07 (d, J ) 8.2 Hz, 1 H), 7.93 (d, J ) 8.2 Hz, 1 H),
7.74-7.70 (m, 3 H), 7.56-7.41 (m, 5 H), 7.35-7.32 (m, 1 H), 6.96
(s, 1 H). 13C{1H} NMR (125 MHz, CDCl3): δ 136.2, 132.5, 131.3,
130.5, 129.1, 129.0, 127.4, 125.9, 125.6, 125.3, 123.9, 121.5, 121.2,
120.6, 119.3, 101.7. IR (neat, cm-1): 3341, 3037, 1602, 1486, 1450,
1390. Anal. Calcd for C18H13N: C, 88.86; H, 5.39. Found: C, 88.62;
H, 5.60.
2-Methyl-3-pentyl-5-trifluoromethylindole 5i. Hydrazone 4h (34
mg, 0.10 mmol), 2-hexanone (62 µL, 0.50 mmol), and p-TsOH‚H2O
(190 mg, 1.0 mmol) were heated in EtOH (1 mL) at reflux for 48 h.
The crude reaction mixture was worked up according to procedure D.
Purification of the crude product by flash chromatography (15% EtOAc/
hexanes) afforded <1 mg of the title compound (<5% yield). 1H NMR
(300 MHz, CDCl3): δ 7.85 (br s, 1 H), 7.76 (s, 1 H), 7.32 (m, 2 H),
2.68 (t, J ) 7.4 Hz, 3 H), 2.40 (s, 3 H), 1.70-1.50 (m, 4 H), 0.95 (t,
J ) 7.4 Hz, 3 H). EI-MS: m/z 241 (M+), 212 (base peak).
“One-Pot” Synthesis of 6-Phenyl-1,2,3,4-tetrahydrocarbazole 3a
from Benzophenone Hydrazone. Benzophenone hydrazone (98 mg,
0.50 mmol) and 4-bromobiphenyl (117 mg, 0.50 mmol) were coupled
according to procedure A. The crude product was heated with
cyclohexanone (78 µL, 0.75 mmol) and p-TsOH‚H2O (190 mg, 1.0
mmol) according to procedure D, except that THF (1 mL) was added
to solubilize the intermediate N-(p-phenyl-phenyl) benzophenone
hydrazone. Purification of the crude product by flash chromatography
(10% EtOAc/hexanes) afforded 3a as a white solid (117 mg, 95% yield).
Spectral data were in accord with those of previously prepared
analytically pure samples.
“One-Pot” Synthesis of 2-Methyl-3-pentyl-5-phenylindole 3b
from Benzophenone Hydrazone. Benzophenone hydrazone (98 mg,
0.50 mmol) and 4-bromobiphenyl (117 mg, 0.50 mmol) were coupled
according to procedure A. The crude product was heated with
2-octanone (70 µL, 0.75 mmol) and p-TsOH‚H2O (190 mg, 1.0 mmol)
according to procedure D, except that THF (1 mL) was added to
solubilize the intermediate N-(4-phenyl-phenyl) benzophenone hydra-
zone. Purification of the crude product by flash chromatography (10%
EtOAc/hexanes) afforded 3b as a clear oil (109 mg, 79% yield). Spectral
data were in accord with those of previously prepared analytically pure
samples.
1
solid (141 mg, 74% yield). Mp: 105-107 °C. H NMR (500 MHz,
CDCl3): δ 7.59 (s, 1 H), 7.34 (d, J ) 8.8 Hz, 1 H), 6.75 (dd, J ) 2.4,
8.3 Hz, 1 H), 3.84 (s, 3 H), 2.72 (q, J ) 7.65 Hz, 2 H), 2.20 (s, 3 H),
1.25 (t, J ) 7.6 Hz, 3 H). 13C{1H} NMR (125 MHz, CDCl3): δ 115.7,
135.6, 135.2, 123.9, 118.5, 108.3, 105.8, 94.4, 55.7, 19.3, 14.1, 8.3.
IR (neat, cm-1): 3416, 2961, 2919, 1570, 1458, 1327. Anal. Calcd for
C12H15NO: C, 76.16; H, 7.99. Found: C, 75.95; H, 7.80.
5,6-Dimethoxy-2-methyl-3-propylindole 5e. Procedure D was used
except that hydrazone 4e (692 mg, 2.10 mmol), 2-hexanone (1.28 mL,
10.4 mmol), water (1.0 mL, 56.0 mmol), and p-TsOH‚H2O (3.96 g,
20.8 mmol) were heated in THF (50 mL) at reflux for 22 h. Purification
of the crude product by flash chromatography (20 f 25% EtOAc/
hexanes) afforded the title compound as a yellow oil (361 mg, 74%
yield). 1H NMR (300 MHz, CDCl3): δ 7.57 (br s, 1 H), 6.94 (s, 1 H),
6.73 (s, 1 H), 3.92 (s, 3 H), 3.85 (s, 3 H), 2.61 (t, J ) 7.3 Hz, 2 H),
2.29 (s, 3 H), 1.63 (sext, J ) 7.3 Hz, 2 H), 0.96 (t, J ) 7.3 Hz, 3 H).
13C{1H} NMR (75 MHz, CDCl3): δ 145.9, 144.3, 129.3, 129.2, 121.5,
111.8, 100.6, 94.4, 60.4, 56.3, 26.2, 23.8, 14.1, 11.6. IR (neat, cm-1):
3369, 2930, 1485, 1464, 1328, 1209, 1158, 756. Anal. Calcd for C14H19-
NO2: C, 72.07; H, 8.21. Found: C, 72.31; H, 8.46.
Procedure E: Alkylation of N-Aryl Benzophenone Hydrazones
4. Lithium diisopropylamide (LDA, 1.2 M/THF) was prepared by
adding diisopropylamine (1.2 equiv) via syringe to THF in an oven-
dried flask that was under Ar and capped with a septum. The flask
(53) Welch, W. M. Synthesis 1977, 645.