PAPER
Functionalisation of the 7-Position of Indoles
3475
Methyl 4-Amino-3-nitro-5-vinylbenzoate (29a)
1H NMR (400 MHz, DMSO-d6): d = 0.43 (s, 9 H), 0.96 (t, J = 7.3
Hz, 3 H), 1.58 (tq, J = 7.6, 7.3 Hz, 2 H), 2.83 (t, J = 7.6 Hz, 2 H),
3.93 (s, 3 H), 8.54 (s, 1 H), 8.57 (s, 1 H), 11.10 (br s, 1 H).
13C NMR (100.6 MHz, DMSO-d6): d = 0.0, 15.0, 25.9, 28.8, 61.1,
111.1, 121.9, 122.8, 124.0, 128.0, 129.2, 135.1, 141.4, 168.6.
A mixture of 3-iodobenzoate 19 (322 mg, 1 mmol, 1 equiv) or 3-
bromobenzoate 21 (1 mmol, 1 equiv), K2CO3 (276 mg, 2 mmol,
2 equiv), Pd(PPh3)4 (115 mg, 0.1 mmol, 0.1 equiv), and DME (6
mL) was stirred under N2 for 30 min. 2,4,6-Trivinylcyclotriborox-
ane–pyridine complex (28a) (240 mg, 1 mmol, 1 equiv) and H2O (1
mL) were added, and the resulting mixture was refluxed (from 19,
1 h; from 21, 3 h), then cooled to r.t. and concentrated in vacuo. The
residue was partitioned between EtOAc (20 mL) and H2O (20 mL),
and the phases were separated. The aqueous phase was extracted
with EtOAc (2 × 10 mL) and the combined organic phases were
washed with H2O (10 mL), dried (MgSO4), and concentrated in vac-
uo. Purification of the residue by flash chromatography (silica gel,
isohexane–EtOAc, 9:1 to 4:1) gave benzoate 29a as a yellow solid.
ESI-MS: m/z = 335.5 [M + H+].
Methyl 7-Nitro-3-propyl-1H-indole-5-carboxylate (31a)
To a soln of indole-5-carboxylate 30 (2.87 g, 8.6 mmol, 1 equiv) in
THF (50 mL) at 0 °C was added 1 M TBAF in THF (10 mL, 10
mmol, 1.2 equiv), and the resulting red mixture was stirred for
5 min. H2O (2 mL) was added and the resulting mixture was parti-
tioned between EtOAc (60 mL) and brine (20 mL). The two layers
were separated and the organic phase was washed with a sat. aq
NaHCO3 soln (2 × 20 mL) and brine (20 mL), dried (MgSO4), and
concentrated in vacuo. Trituration of the residue with MeCN gave
indole-5-carboxylate 31a.
Yield: 196 mg (88%) (from 19), 171 mg (77%) (from 21); mp 138–
140 °C.
1H NMR (400 MHz, DMSO-d6): d = 3.84 (s, 3 H), 5.46 (dd, J =
10.8, 1.2 Hz, 1 H), 5.79 (dd, J = 17.2, 1.2 Hz, 1 H), 7.03 (dd, J =
17.2, 10.8 Hz, 1 H), 7.83 (br s, 2 H), 7.99 (d, J = 2.0 Hz, 1 H), 8.53
(d, J = 2.0 Hz, 1 H).
13C NMR (100.6 MHz, CDCl3): d = 52.0, 115.8, 118.6, 127.3,
127.5, 130.8, 130.9, 131.5, 145.8, 164.7.
ESI-MS: m/z = 223.2 [M + H+].
Yellow solid; yield: 2.0 g (89%); mp 162–164 °C.
1H NMR (400 MHz, CDCl3): d = 1.02 (t, J = 7.2 Hz, 3 H), 1.75 (tq,
J = 7.6, 7.2 Hz, 2 H), 2.79 (t, J = 7.6 Hz, 2 H), 4.00 (s, 3 H), 7.22 (s,
1 H), 8.65 (d, J = 0.4 Hz, 1 H), 8.84 (d, J = 0.4 Hz, 1 H), 9.85 (br s,
1 H).
13C NMR (100.6 MHz, CDCl3): d = 14.0, 23.4, 26.8, 52.4, 120.1,
120.5, 121.2, 124.6, 128.5, 128.6, 131.6, 132.1, 166.4.
Methyl 4-Amino-3-(1-methylenepropyl)-5-nitrobenzoate (29b)
A mixture of 3-iodobenzoate 19 (3.22 g, 10 mmol, 1 equiv),
Pd(PPh3)4 (575 mg, 0.5 mmol, 0.05 equiv), and DME (60 mL) was
stirred at r.t. under N2 for 30 min. K2CO3 (1.5 g, 11 mmol, 1.1
ESI-MS: m/z = 261.2 [M – H]– (tR = 3.28 min).
Methyl 7-Nitro-2-propyl-1H-indole-5-carboxylate (31b)
Indole-5-carboxylate 31b was obtained as a by-product during the
synthesis of indole-5-carboxylate 30 and was not separated from in-
dole-5-carboxylate 31a.
1H NMR (400 MHz, DMSO-d6): d = 0.96 (t, J = 7.3 Hz, 3 H), 1.72
(tq, J = 7.6, 7.3 Hz, 2 H), 2.74 (t, J = 7.6 Hz, 2 H), 3.91 (s, 3 H), 6.60
(s, 1 H), 8.46 (s, 1 H), 8.48 (s, 1 H), 12.04 (br s, 1 H).
equiv),
2,4,6-tri(1-methylenepropyl)cyclotriboroxane–pyridine
complex (28b; prepared from 1-methylenepropylmagnesium bro-
mide by a published procedure20a) (3.4 g, 10 mmol, 1 equiv), and
H2O (20 mL) were added. The mixture was refluxed for 1.5 h, and
then cooled to r.t. and concentrated in vacuo. The residue was par-
titioned between EtOAc (50 mL) and H2O (20 mL), and the phases
were separated. The aqueous phase was extracted with EtOAc (2 ×
10 mL) and the combined organic phases were washed with sat. aq
NaHCO3 soln (15 mL) and then brine (15 mL), dried (MgSO4), and
concentrated in vacuo. Purification of the residue by flash chroma-
tography (silica gel, isohexane–EtOAc, 9:1 to 3:1) gave methyl ben-
zoate 29b as a yellow solid.
ESI-MS: m/z = 263.4 [M + H+].
Methyl 3-Bromo-4-[(E/Z)-but-2-enylamino]-5-nitrobenzoate
(33)
To a soln of benzoate 25 (67.5 g, 0.16 mol, 1 equiv) in MeOH (1 L)
was added K2CO3 (24.1 g, 0.17 mol, 1.1 equiv) and the resulting red
soln was stirred for 45 min at r.t. Most of the K2CO3 was collected
by filtration, and most of the MeOH was removed in vacuo. When
approximately 300 mL of MeOH remained, a yellow precipitate
formed. This was collected by filtration and washed with MeOH.
The filtrate and washings were evaporated in vacuo and the residue
was dissolved in EtOAc (150 mL). The organic soln was washed
with brine (2 × 40 mL), dried (MgSO4), and concentrated in vacuo.
Purification of the residue by flash chromatography (silica gel, iso-
hexane–EtOAc, 9:1 then 4:1) gave benzoate 33 as a red solid; yield:
8.9 g (17%). The yellow precipitate was dissolved in EtOAc (300
mL). The soln was washed with brine (2 × 50 mL), dried (MgSO4),
and concentrated in vacuo to give benzoate 33 as a yellow solid;
yield: 34.5 g (66%).
Yield: 2.38 g (95%); mp 117–119 °C.
1H NMR (400 MHz, CDCl3): d = 1.09 (t, J = 7.2 Hz, 3 H), 2.37 (q,
J = 7.2 Hz, 2 H), 3.90 (s, 3 H), 5.15 (s, 1 H), 5.47 (s, 1 H), 6.70 (br
s, 2 H), 7.81 (d, J = 2.0 Hz, 1 H), 8.79 (d, J = 2.0 Hz, 1 H).
13C NMR (100.6 MHz, CDCl3): d = 12.4, 30.2, 52.2, 116.6, 117.7,
127.7, 131.7, 132.1, 134.3, 145.1, 146.4, 165.7.
ESI-MS: m/z = 251.2 [M + H+].
Methyl 7-Nitro-3-propyl-2-(trimethylsilyl)-1H-indole-5-
carboxylate (30)
To a soln of benzoate 19 (6.9 g, 21.4 mmol, 1 equiv) in DMF (200
mL) under N2 were added LiCl (907 mg, 21.4 mmol, 1 equiv), tri-
methyl(pent-1-ynyl)silane (19.7 mL, 107 mmol, 5 equiv), K2CO3
(14.8 g, 107 mmol, 5 equiv), and Pd(OAc)2 (480 mg, 2.14 mmol, 0.1
equiv). The mixture was stirred at 100 °C for 3 h and then cooled to
r.t. and concentrated in vacuo. The residue was partitioned between
EtOAc (60 mL) and H2O (20 mL), and the layers were separated.
The organic phase was filtered through Hyflo to remove some insol-
uble material and then washed with brine (20 mL), dried (MgSO4),
and concentrated in vacuo. The residue was purified by flash chro-
matography (silica gel, isohexane–EtOAc, 95:5 then 9:1).
Mp 54–56 °C.
1H NMR (400 MHz, DMSO-d6): major isomer: d = 1.58 (d, J = 6.4
Hz, 3 H), 3.80 (m, 2 H), 3.83 (s, 3 H), 5.33 (m, 1 H), 5.54 (m, 1 H),
6.94 (t, J = 6.0 Hz, 1 H), 8.18 (s, 1 H), 8.26 (s, 1 H). Minor isomer
d = 1.58 (d, J = 6.4 Hz, 3 H), 3.83 (s, 3 H), 3.93 (m, 2 H), 5.29 (m,
1 H), 5.54 (m, 1 H), 7.04 (t, J = 5.2 Hz, 1 H), 8.18 (s, 1 H), 8.27 (s,
1 H).
13C NMR (100.6 MHz, DMSO-d6): major isomer: d = 17.5, 47.4,
52.3, 113.0, 117.7, 126.4, 127.4, 129.9, 136.1, 136.8, 143.2, 163.7.
ESI-MS: m/z = 330.8, 332.9 [M + H+].
Yellow solid; yield: 3.9 g (53%); mp 119–120 °C.
Synthesis 2006, No. 20, 3467–3477 © Thieme Stuttgart · New York