PAPER
Synthesis of Indole-Based Heterocycles
Yield: 1.5 g (64%); light-brown powder.
1H NMR (400 MHz, C6D6): d = 8.23 (d, J = 8.4 Hz, 1 H), 7.76 (d,
J = 7.7 Hz, 1 H), 7.68 (m, 1 H), 7.66 (m, 1 H), 7.55 (s, 1 H), 7.04 (t,
J = 7.3 Hz, 2 H), 6.61 (m, 3 H), 4.17 (dd, J = 13.3, 1.3 Hz, 1 H),
3.18 (d, J = 13.4 Hz, 1 H), 2.70 (td, J = 8.2, 2.3 Hz, 1 H), 2.59 (dd,
J = 11.2, 4.7 Hz, 1 H), 2.50–2.32 (m, 6 H), 1.89 (q, J = 8.9 Hz, 1 H),
1.78 (m, 1 H), 1.53 (m, 5 H).
1849
Table 3 Synthesis of Gramines from Unprotected 1H-Indole-3-car-
boxylates 1a–d Using DIBAL-H
O
O
0.5 Al2Me4Z2
(3a–h)
OEt
Z
R1
R1
1) PhMe, 100 °C
2) H2O, – CH4
N
N
H
H
13C NMR (100 MHz, C6D6): d = 138.6, 136.0, 132.8, 128.6, 126.4,
124.7, 124.1, 123.0, 122.3, 120.9, 113.8, 62.7, 61.9, 54.7, 54.6,
50.0, 30.3, 23.5, 22.6.
1a–d
2a–k
Z
1) n-BuLi, 0–5 °C
R1
2) DIBAL-H, 50 °C
H3O+
Anal. Calcd for C24H27N3O3S: C, 65.8; H, 6.22; N, 9.6. Found: C,
66.1; H, 6.43; N, 9.4.
N
H
7a–k
Reduction of Indole-3-carboxamides Using DIBAL-H:
3-[(3-Methylpiperidin-1-yl)methyl]-1H-indole (7f); Typical
Procedure
Entry Indole R1
Z
Yield of 2 Yield of 7
(%)
(%)
(1H-Indol-3-yl)(3-methylpiperidin-1-yl)methanone (2f; 2.3 g, 9.5
mmol) was dissolved in toluene (50 mL) inside a 100 mL reaction
flask, under nitrogen. A solution of n-BuLi (2.5 M in hexanes, 3.8
mL, 9.5 mmol) was added to the reaction mixture over a 10 min pe-
riod at 0–5 °C, resulting in a mild exotherm. After stirring for an ad-
ditional 15 min, a solution of DIBAL-H in toluene (1.5 M, 6.6 mL,
10 mmol) was added to the reaction mixture over a 5 min period at
0–5 °C. No exotherm was observed. The reaction mixture was al-
lowed to warm to r.t., then stirred at 50 °C for 16 h. After cooling to
r.t., MeOH (1.9 mL) was added to the reaction mixture over a 10
min period, resulting in the formation of solids that were removed
by Buchner filtration. The filtrate was concentrated under reduced
vacuum, then purified by flash chromatography on silica gel (THF–
EtOH, 10:1) to give 7f.
Yield: 1.7 g (75%); light-brown powder; mp 145–148 °C (Lit.9
144–146 °C).
IR (ATR): 3230 (NH), 2510 (CH), 1555, 1501, 1335, 885, 730 cm–l.
1H NMR (400 MHz, DMSO-d6): d = 10.88 (s, 1 H), 7.33 (d, J = 8.1
Hz, 1 H), 7.18 (d, J = 2.2 Hz, 1 H), 7.05 (t, J = 7.3 Hz, 1 H), 6.96 (t,
J = 7.3 Hz, 1 H), 3.56 (s, 2 H), 2.82–2.72 (br, 2 H), 1.86–1.76 (br t,
1 H), 1.66–1.34 (br, 5 H), 0.86–0.73 (m, 4 H).
1
2
1a
H
H
NMe2
2a (59)
2b (42)
7a (85)
7b (79)
N(n-Pr)2
3
H
2c (55)
7c (73)
N
Me
4
5
6
7
H
H
H
H
2d (58)
2e (41)
2f (62)
2g (61)
7d (81)
7e (65)
7f (75)
7g (79)
N
N
N
N
13C NMR (100 MHz, DMSO-d6): d = 136.7, 128.1, 124.8, 121.3,
119.5, 118.7, 111.7, 111.6, 61.8, 54.2, 53.8, 33.2, 31.1, 25.6, 20.1.
8
H
2h (75)
7h (74)
N
Anal. Calcd for C15H20N2: C, 78.90; H, 8.83; N, 12.27. Found: C,
78.56; H, 8.59; N, 12.33.
N
9
10
11
1b
1c
1d
5-MeO NMe2
6-MeO NMe2
2i (65)
2j (63)
2k (57)
7i (77)
7j (81)
7k (63)
Synthesis of 1H-Indole-3-carboxamides: (S)-(1H-Indol-3-yl)[2-
(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]methanone (2h); Typi-
cal Procedure
5-Br
NMe2
Ethyl indole-3-carboxylate (1a; 3.4 g, 0.019 mol) was dissolved in
toluene (60 mL) inside a 250 mL reaction flask under a N2 atmo-
sphere. A toluene solution of 3h (100 mL, 0.019 mol, ~0.19 M) was
added to the slurry over 10 min at r.t., resulting in substantial gas
evolution. The reaction mixture was refluxed for 16 h, then allowed
to cool to r.t. with stirring. H2O (7 mL) was added to the reaction
mixture over 5 min to give a slurry (the addition of H2O was mod-
erately exothermic with moderate gas evolution). Solids were re-
moved by filtration and washed with THF (100 mL). The filtrates
were combined and concentrated to a solid under reduced pressure
and the residue was purified by flash chromatography on silica gel
(THF–EtOH, 10:1) to give 2h.
Synthesis of N-(Phenylsulfonyl)indole-3-carboxamides:
(S)-[1-(Phenylsulfonyl)-1H-indol-3-yl][2-(pyrrolidin-1-ylmeth-
yl)pyrrolidin-1-yl]methanone (5h); Typical Procedure
Ethyl (N-phenylsulfonyl)indole-3-carboxylate (4a; 1.75 g, 0.006
mol) was dissolved in toluene (3 mL) inside a 100 mL reaction flask
under N2. A toluene solution of 3h (20 mL, 0.006 mol, ~0.28 M)
was added to the slurry over 10 min at r.t., resulting in a 2–3 °C exo-
therm. The reaction mixture was heated to reflux for 18 h, allowed
to cool to r.t., then H2O (2 mL) was added to the reaction mixture
over 10 min, resulting in gas evolution and a mild exotherm. Solids
were removed by filtration to yield a dark biphasic filtrate. The or-
ganics were collected, washed with H2O (5 mL) and brine (5 mL),
and then dried over anhydrous Na2SO4. The organics were concen-
trated under reduced pressure, then purified by flash chromatogra-
phy on silica gel (THF–EtOH, 10:1) to give a dark, tacky solid.
Triturating the tacky solid with cyclohexane (50 mL) yielded 5h.
Yield: 4.5 g (75%); free-flowing, white powder; mp 139–140 °C.
IR (ATR): 3230, 2510 (NH, CH), 1725, 1654, 1555, 1501, 1335,
885, 730 cm–1.
1H NMR (400 MHz, C6D6): d = 10.90 (s, 1 H), 8.35 (d, J = 7.7 Hz,
1 H), 7.39 (d, J = 7.7 Hz, 1 H), 7.20–7.13 (m, 2 H), 6.91 (br, 1 H),
4.75–4.48 (br, 1 H), 3.31–3.03 (br, 2 H), 2.98–2.72 (br, 1 H), 2.63–
Synthesis 2009, No. 11, 1846–1850 © Thieme Stuttgart · New York