Palladium-catalyzed indole and azaindole synthesis by direct annulation of electron-poor o-chloroanilines and o-chloroaminopyridines with aldehydes

Article abstract of DOI:10.1055/s-0028-1083225

A practical process for the synthesis of 2-unsubstituted indoles and azaindoles has been developed by the palladium-catalyzed direct annulation of electron-poor o-chloro/bromoanilines and o-chloroaminopyridines with aldehydes. Coupled with the previous results of Jia and Zhu, this allows rapid access to a variety of 2-unsubstituted indoles and azaindoles starting from simple and easily accessible precursors. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1083225

PAPER
3981
Palladium-Catalyzed Indole and Azaindole Synthesis by Direct Annulation of
Electron-Poor o-Chloroanilines and o-Chloroaminopyridines with Aldehydes
S
ynthesis of 2-U
h
nsubstituted
e
Indoles an
n
d
A
zaindole
g
ren Xu, Weimin Hu, Fengying Zhang, Qingjiang Li, Zhiyao Lü, Lihe Zhang, Yanxing Jia*
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University,
38 Xueyuan Road, Beijing 100191, P. R. of China
Fax +86(10)82805166; E-mail: yxjia@bjmu.edu.cn
Received 4 June 2008; revised 4 August 2008
There are examples in the literature of electron-rich aryl
Abstract: A practical process for the synthesis of 2-unsubstituted
indoles and azaindoles has been developed by the palladium-cata-
lyzed direct annulation of electron-poor o-chloro/bromoanilines
and o-chloroaminopyridines with aldehydes. Coupled with the pre-
chlorides behaving differently than electron-deficient
ones in palladium-catalyzed reactions.10 Considering the
complexity of this palladium-catalyzed process, we
vious results of Jia and Zhu, this allows rapid access to a variety of thought that by testing combinations of ligands, solvents
2-unsubstituted indoles and azaindoles starting from simple and
easily accessible precursors.
and bases, we could discover an efficient condition for the
annulation of electron-poor o-chloro/bromoanilines with
Key words: indole, azaindole, palladium, annulation, ligand
aldehydes. Herein, we are pleased to report a general pro-
cedure for the synthesis of highly benzofunctionalized 2-
unsubstituted indoles and azaindoles by reaction of elec-
tron-poor o-chloro/bromoanilines and o-chloroaminopy-
ridines with a variety of aldehydes.
The indole nucleus is a prominent structural motif abun-
dantly found in a wide variety of bioactive natural prod-
ucts and pharmaceuticals.1 After extensive research over
a hundred years, a variety of well-documented methods
for the preparation of functionalized indoles are now
available.2 However, the development of general, mild,
and efficient methods from simple and easily accessible
precursors are of continued interest.3 In this context, pal-
ladium-catalyzed reactions, generally tolerant of many
functional groups, are widely applied to the preparation of
the indole scaffold and provide alternatives to traditional
methods.4,5
In our initial attempts, ligands 1a–l (Figure 1) were tested
for the reaction of 2-chloro-5-nitroaniline (2a) with 3-
(3,4,5-trimethoxyphenyl)propanal (3a) in the presence of
Pd(dba)2 and KOAc in DMA (Scheme 1 and Table 1).
Quickly, it was revealed that the choice of the ligand was
again critical. Of the ligands tested, t-Bu3P·HBF4 was the
most efficient and afforded the desired indole 4a in 43%
yield, albeit with the formation of 12% dechloro product
(entry 12). The addition of water, presumably preventing
aldol condensation of aldehydes, gave the same yield of
the desired product (entry 13). The effects on yield with
varying equivalents of aldehyde or aniline were also ex-
amined. When 3.0 equivalents of aldehyde were used, the
yield increased to 58% (entry 14) contemporaneous with
the formation of 2-(3,4,5-trimethoxybenzyl)-5-(3,4,5-tri-
methoxyphenyl)pent-2-enal (5) in 44% (Scheme 1). The
use of 5 mol% of commercially available [Pd(t-Bu3P)2]
gave result similar to that of Pd(dba)2 and t-Bu3P·HBF4
(entry 16). We also tested this reaction under microwave
In 1997, Chen and co-workers at Merck Research Labora-
tories reported an efficient method for the synthesis of in-
doles by coupling of o-iodoaniline with cyclic ketones;
acyclic ketones were found to be less efficient, and sur-
prisingly, aldehydes have not been used as a reaction part-
ner.6 Recently, Jia and Zhu have extended this method for
the synthesis of highly benzofunctionalized 2-unsubstitut-
ed indoles, including enantiomerically pure tryptophan
derivatives, by using readily available aldehydes as start-
ing materials. This method has been successfully applied
to the synthesis of complestatin and suaveolindole7 and
later extended by replacing the o-iodoanilines with much
cheaper and readily available electron-rich or -neutral
o-chloro/bromoanilines as the reaction partners by using
X-Phos, a bulky electron-rich monophosphine, as the
ligand.8,9 However, under optimized conditions, reaction
of electron-poor o-chloro/bromoanilines with aldehydes
gave the desired products in unsatisfactory yields (around
10–20%), together with significant amounts of the re-
duced arene compounds.
1a R1 = R2 = R3 = H, R = t-Bu
1b R1 = R2 = R3 = H, R = Cy
1c R1 = NMe2, R2 = R3 = H, R = t-Bu
PR2
R2
1d R1 = NMe2, R2 = R3 = H, R = Cy
R1
1e R1 = Me, R2 = R3 = H, R = t-Bu
1f R1 = Me, R2 = R3 = H, R = Cy
1g R1 = R2 = R3 = i-Pr, R = t-Bu
1h R1 = R2 = R3 = i-Pr, R = Cy
R3
PCy2
i-Pr
i-Pr
1k PCy3
1l t-Bu3P•HBF4
O
PPh2
PPh2
1i
1j
i-Pr
SYNTHESIS 2008, No. 24, pp 3981–3987
Advanced online publication: 01.12.2008
DOI: 10.1055/s-0028-1083225; Art ID: F12608SS
x
x.
x
x
.
2
0
0
8
Figure 1 Ligands tested for the annulation of 2-chloro-5-nitro-
aniline (2a) with 3-(3,4,5-trimethoxyphenyl)propanal (3a)
© Georg Thieme Verlag Stuttgart · New York

3982
Z. Xu et al.
PAPER
OMe
OMe
Table 1 Optimization of Conditions for the Annulation of 2-Chlo-
ro-5-nitroaniline (2a) with 3-(3,4,5-Trimethoxyphenyl)propanal (3a)a
Pd(dba)2
L, KOAc
Cl
O
+
DMA
120 °C
Yield (%)b
<1
O2N
NH2
Entry
1
Ligand
1a
1b
1c
1d
1e
1f
Base
OMe
2a
3a
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
DABCO
KOAc
OMe
OMe
O
OMe
2
<1
3
<1
OMe
N
H
4a
O2N
MeO
OMe
OMe
4
<5
5
MeO
5
<1
OMe
6
14
Scheme 1 Annulation of 2-chloro-5-nitroaniline (2a) with 3-(3,4,5-
trimethoxyphenyl)propanal (3a)
7
1g
1h
1i
<1
8
15
irradiation at 160 °C for 30 minutes, but it did not show
any improvement.
9
<5
Once reliable conditions to synthesize indoles were estab-
lished, we proceeded to examine the substrate scope with
respect to electron-deficient o-chloroanilines (Table 2).
The method proved to be effective for a range of electron-
deficient o-chloroanilines bearing a variety of functional
groups, such as nitro (entries 1, 2 and 3), ester (entries 5
and 6), keto (entry 7), and trifluoromethyl (entry 8). The
steric hindrance in 2b could not be suppressed under these
conditions, and the yield was not increased even by vary-
ing bases, solvents, and equivalents of substrate (entry 4).
As expected, the electron-deficient o-bromoanilines re-
10
11
12
13c
14
15
16
1j
<5
1k
1l
<1
43
1l
43
1l
58d
22
1l
–
58e
acted with similar efficiency (entries 9, 10, and 11). The a General reaction conditions: concentration = 0.2 M in DMA.
major side product frequently observed is the dehaloge-
nated starting material, the result of a reductive process.
Not surprisingly, this catalyst system proved to be also ef-
fective, though inferior relative to X-phos, for the reaction
of electron-rich or -neutral o-chloroanilines with alde-
hydes and gave the desired indoles in moderate
yields.9a,6b,11
Pd(dba)2 (0.05 equiv), ligand (0.10 equiv), 2-chloro-5-nitroaniline
(2a; 1.0 equiv), 3-(3,4,5-trimethoxyphenyl)propanal (3a; 1.0 equiv),
and KOAc (3.0 equiv) at 120 °C.
b Isolated yield.
c H2O (13%) was used as an additive.
d Aldehyde = 3.0 equiv.
e Pd(t-Bu3P)2 = 0.05 equiv and aldehyde = 3.0 equiv.
Table 2 Pd-Catalyzed Indole Synthesis by Annulation of Electron-Poor o-Chloro/bromoanilines with Aldehydesa
R
Pd(dba)2
X
t-Bu3P•HBF4
R
+
EWG
EWG
O
KOAc, DMA
120 °C
N
NH2
H
X = Cl, Br
2
3
4
Entry
o-Chloro/bromoaniline
Product
Yield (%)b
58
OMe
OMe
Cl
1
2
N
H
O2N
O2N
NH2
OMe
2a
4a
2a
65
N
H
O2N
4b
Synthesis 2008, No. 24, 3981–3987 © Thieme Stuttgart · New York

PAPER
Synthesis of 2-Unsubstituted Indoles and Azaindoles
3983
Table 2 Pd-Catalyzed Indole Synthesis by Annulation of Electron-Poor o-Chloro/bromoanilines with Aldehydesa (continued)
R
Pd(dba)2
X
t-Bu3P•HBF4
R
+
EWG
EWG
O
KOAc, DMA
120 °C
N
NH2
H
X = Cl, Br
2
3
4
Entry
o-Chloro/bromoaniline
Product
Yield (%)b
65
CO2Me
3
4
2a
N(Boc)2
N
H
O2N
4c
CO2Me
CO2Me
Cl
25
N
NH2
H
2b
4d
4e
Cl
5
6
71
71
N
H
NH2
CO2Me
CO2Me
2c
Cl
N
H
MeO2C
NH2
MeO2C
2d
4f
Cl
7
41
NH2
N
H
O
O
2e
4g
OMe
Cl
8
9
51
41
OMe
N
H
F3C
F3C
NH2
OMe
OMe
2f
4h
OMe
OMe
O2N
O2N
Br
N
H
NH2
2g
4i
Ph
NC
Br
NC
10
11
61
68
N
NH2
H
2h
4j
Br
N
O2N
O2N
NH2
H
2i
4k
a General reaction conditions: concentration = 0.2 M in DMA. Pd(dba)2 (0.05 equiv), t-Bu3P·HBF4 (0.10 equiv), o-chloro/bromoaniline (1.0
equiv), aldehyde (3.0 equiv), KOAc (3.0 equiv) at 120 °C.
b Isolated yield.
Synthesis 2008, No. 24, 3981–3987 © Thieme Stuttgart · New York

3984
Z. Xu et al.
PAPER
Azaindole ring systems have attracted considerable inter- We next examined the reaction of electron-deficient o-
est due to their applications in medicinal relevance, mate- chloroaminopyridines under the aforementioned condi-
rial synthesis, coordination chemistry, and they are tions. Soon it was proved that these substrates are more
frequently exploited as indole bioisosteres in the design of challenging. Only 2-amino-3-chloro-5-trifluoromethyl-
biologically interesting molecules.12,13 Synthetic routes to pyridine (6d) afforded the desired product in 56% yield
azaindole using classical indole formation methods are of- (Table 3, entry 6), while other substrates did not react ef-
ten not efficient or even fail because of the electron-defi- ficiently and gave the azaindoles in low yields.
cient nature of the pyridine ring. More recently, most
We envisioned that the inefficiency of the reaction maybe
practical and mild methods for the synthesis of azaindoles
due to electronic effects of pyridine ring or to coordina-
are based on transition metal catalysis. Therefore, we
tion of Pd by the lone pair of electrons on the pyridine ni-
sought to extend our palladium-catalyzed methodology to
trogen at some point of the catalytic cycle. Thus, this
effect would be reduced by increasing the temperature or
the synthesis of azaindoles.
choosing the proper base. As anticipated, eventually, it
Table 3 Pd-Catalyzed Azaindole Synthesis by Annulation of
was found that this problem could be alleviated by using
DABCO as a base and using a higher temperature
(150 °C). It should be emphasized that the yield was lower
under microwave irradiation conditions than thermal
heating conditions in this one-pot azaindole synthesis.14
o-Chloroaminopyridines with Aldehydesa
R
Pd(dba)2
Cl
t-Bu3P•HBF4
R
R1
R1
+
N
N
O
DABCO, DMA
150 °C
N
NH2
H
6
3
7
To illustrate the scope of this methodology, a variety of
azaindoles were synthesized under our standard condi-
tions (Table 3). Both 3-amino-2-chloropyridine (6a) and
3-amino-4-chloropyridine (6b) could react with aliphatic
aldehyde and phenylacetaldehyde to give the desired
products (entries 1–4). However, 2-amino-3,5-dichloro-
pyridine (6c) and 2-amino-3-chloro-5-trifluoromethylpy-
ridine (6d) only reacted with phenylacetaldehyde, but not
with aliphatic aldehydes (entries 5 and 6). Unfortunately,
to date, all attempts to perform this reaction with 4-amino-
3-bromopyridine have been unsuccessful.
Entry o-Chloroaminopyridine Product
Yield
(%)b
N
Cl
N
1
2
3
4
44
N
H
NH2
6a
6a
7a
7b
Ph
N
68
N
H
In summary, we have developed a practical one-pot pro-
cedure for the synthesis of highly benzofunctionalized 2-
unsubstituted indoles and azaindoles by the reaction of
electron-poor o-chloro/bromoanilines and o-chloroami-
nopyridines with a variety of aldehydes. Coupled with the
previous results of Jia and Zhu, this allows rapid access to
a variety of 2-unsubstituted indoles and azaindoles start-
ing from simple and easily accessible precursors. Further
applications of this chemistry to the synthesis of natural
products are currently in progress and will be reported in
due course.
Cl
76c
50c
N
N
N
H
NH2
6b
7c
Ph
6b
N
N
H
7d
Ph
Cl
Cl
Cl
5
6
42
Melting points were recorded using XT-4A digital micro-melting
apparatus. IR spectra were recorded on a NEXUS-470 FRIR (Nico-
let) spectrometer. 1H and 13C NMR spectra were recorded on Bruker
AC-300 spectrometer, JEOL JNM-AL 300 spectrometer, and Vari-
an INOVA-500 spectrometer. High resolution mass spectra
(HRMS) were obtained using a Bruker APEX IV FT-MS (ESI) in-
strument. Flash chromatography was performed using silica gel
from Qingdao Mar. Chem. Ind. Co. Ltd. (200–300 mesh). Anilines
2a,f–i and o-chloroaminopyridines 6a–d are commercially avail-
able. Anilines 2c–e were prepared following known procedures.
N
H
N
NH2
N
6c
7e
Ph
F3C
Cl
F3C
31
56d
N
N
NH2
N
H
6d
7f
a General reaction conditions: concentration = 0.2 M in DMA.
Pd(dba)2 (0.05 equiv), t-Bu3P·HBF4 (0.10 equiv), o-chloroaminopyri-
dine (1.0 equiv), aldehyde (3.0 equiv), and DABCO (3.0 equiv) at
Methyl 3-Amino-2-chlorobenzoate (2b)
150 °C.
To a solution of 2-chloro-3-nitrobenzoic acid (403 mg, 2.0 mmol)
in anhyd MeOH (8 mL) was added dropwise SOCl2 at 0 °C (ice
bath). After the addition was over, the mixture was warmed to 40 °C
and stirred overnight until the starting material had disappeared
(monitored by TLC). The mixture was then evaporated to dryness.
The product was used directly for the next step without purification.
The above methyl 2-chloro-3-nitrobenzoate and SnCl2·2H2O (2.26
b Isolated yield.
c At 120 °C.
d KOAc = 3.0 equiv at 120 °C.
Synthesis 2008, No. 24, 3981–3987 © Thieme Stuttgart · New York

PAPER
Synthesis of 2-Unsubstituted Indoles and Azaindoles
3985
g, 10.0 mmol, 5.0 equiv) was dissolved in anhyd EtOH (5 mL) and
the mixture was stirred at 70 °C for 30 min under argon. The mix-
ture was cooled to r.t. and made slightly basic (pH 7–8) by aq sat.
NaHCO3. The mixture was extracted with EtOAc (2 × 15 mL), and
the combined organic phases were washed with brine (3 × 15 mL),
dried (Na2SO4), and concentrated in vacuo. The residue was puri-
fied by silica gel eluting with 60% CH2Cl2 in petroleum ether (bp
60–90 °C); yield: 362 mg (98%); yellowish oil.
1H NMR (300 MHz, CDCl3): d = 7.06 (d, J = 7.5 Hz, 1 H), 7.00 (t,
J = 7.5 Hz, 1 H), 6.79 (d, J = 7.5 Hz, 1 H), 4.16 (br s, 2 H), 3.83 (s,
3H).
HRMS (ESI): m/z calcd for C13H16N2O2 + Na (M + Na)+: 255.1109;
found: 255.1122.
Methyl 3-Pentyl-1H-indole-4-carboxylate (4d)
Purified by FCC (PE–EtOAc, 5:1); oil.
IR (KBr): 3367, 2954, 2928, 2857, 1702, 1615, 1435, 1345, 1277,
1200, 1143, 922, 806, 777, 750 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.21 (br s, 1 H), 7.56 (dd, J = 0.6,
7.5 Hz, 1 H), 7.46 (dd, J = 0.6, 7.5 Hz, 1 H), 7.16 (t, J = 7.5 Hz, 1
H), 7.07 (d, J = 2.4 Hz, 1 H), 3.95 (s, 3 H), 2.83 (t, J = 6.9 Hz, 2 H),
1.50–1.58 (m, 2 H), 1.24–1.33 (m, 4 H), 0.87 (t, J = 7.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 169.4, 137.7, 124.3, 124.2, 124.1,
3-(3,4,5-Trimethoxybenzyl)-6-nitro-1H-indole (4a); Typical
Procedure
122.1, 120.7, 117.6, 115.0, 51.9, 31.9, 30.2, 27.2, 22.7, 14.1.
HRMS (ESI): m/z calcd for C15H20NO2 (M + H)+: 246.14886;
found: 246.14839.
A solution of 2-chloro-5-nitroaniline (2a; 52 mg, 0.3 mmol), 3-
(3,4,5-trimethoxyphenyl)propanal (3a; 202 mg, 0.9 mmol), and
KOAc (88 mg, 0.9 mmol) in anhyd DMA (1.5 mL) was degassed
for 20 min. Pd(dba)2 (8.6 mg, 0.015 mmol) and t-Bu3P·HBF4 (8.7
mg, 0.03 mmol) were added, and the resulting mixture was heated
at 120 °C for 9 h. The mixture was cooled to r.t. and diluted with
H2O (15 mL) and the aqueous phase was extracted with EtOAc
(2 × 15 mL). The combined organic phases were washed with brine
(3 × 15 mL), dried (Na2SO4), and evaporated to dryness under re-
duced pressure. Purification of the crude product by flash column
chromatography (FCC) (PE–EtOAc, 7:3) provided the desired
product 4a; yield: 59.5 mg (58%); mp 166–167 °C (Table 2).
Methyl 3-Hexyl-1H-indole-7-carboxylate (4e)
Purified by FCC (PE–EtOAc, 60:1); mp 47–48 °C.
IR (CHCl3): 3422, 2948, 2924, 2853, 1686, 1587, 1439, 1267, 1200,
1142, 1075, 1059, 990, 898, 807 cm–1.
1H NMR (500 MHz, CDCl3): d = 9.59 (br s, 1 H), 7.89 (d, J = 7.5
Hz, 1 H), 7.83 (d, J = 7.5 Hz, 1 H), 7.14 (t, J = 7.5 Hz, 1 H), 7.08
(br s, 1 H), 3.99 (s, 3 H), 2.77 (t, J = 8.0 Hz, 2 H), 1.69–1.75 (m, 2
H), 1.40–1.42 (m, 2 H), 1.32–1.35 (m, 4 H), 0.90 (t, J = 7.0 Hz, 3
H).
13C NMR (125 MHz, CDCl3): d = 168.0, 136.2, 128.9, 124.6, 124.1,
122.0, 118.2, 117.1, 112.3, 51.8, 31.7, 30.2, 29.3, 25.0, 22.7, 14.1.
IR (CHCl3): 3361, 2936, 1590, 1505, 1456, 1418, 1311, 1240, 1123,
1057, 1001, 963, 895, 822 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.90 (br s, 1 H ), 8.33 (d, J = 2.1
Hz, 1 H), 7.98 (dd, J = 2.1, 8.7 Hz, 1H), 7.55 (d, J = 8.7 Hz, 1 H),
7.25 (d, J = 2.7 Hz, 1 H), 6.49 (s, 2 H), 4.07 (s, 2 H), 3.84 (s, 3 H),
3.80 (s, 6 H).
HRMS (ESI): m/z calcd for C16H22NO2 (M + H)+: 260.1651; found:
260.1658.
Methyl 3-Hexyl-1H-indole-6-carboxylate (4f)
Purified by FCC (PE–EtOAc, 10:1); mp 83–84 °C.
13C NMR (75 MHz, CDCl3): d = 153.2, 143.3, 136.3, 136.0, 134.9,
132.0, 128.5, 118.9, 116.5, 114.9, 108.2, 105.6, 60.9, 56.1, 31.6.
IR (CHCl3): 3322, 2948, 2922, 2854, 1689, 1623, 1563, 1503, 1458,
1434, 1356, 1302, 1272, 1210, 1086, 984, 879, 827 cm–1.
HRMS (ESI): m/z calcd for C18H18N2O5 + Na (M + Na)+: 365.1113;
found: 365.1130.
1H NMR (300 MHz, CDCl3): d = 8.40 (br s, 1 H), 8.13 (d, J = 1.5
Hz, 1 H), 7.82 (dd, J = 1.5 8.4 Hz, 1 H), 7.63 (d, J = 8.4 Hz, 1 H),
7.13 (d, J = 2.4 Hz, 1 H), 3.95 (s, 3 H), 2.76 (t, J = 7.5 Hz, 2 H), 1.73
(m, 2 H), 1.42 (m, 2 H), 1.30–1.43 (m, 4 H), 0.91 (t, J = 7.2 Hz, 3
H).
13C NMR (75 MHz, CDCl3): d = 168.4, 135.6, 131.2, 124.7, 123.3,
120.0, 118.5, 117.5, 113.5, 51.9, 31.7, 30.1, 29.2, 25.0, 22.6, 14.1.
2-(3,4,5-Trimethoxybenzyl)-5-(3,4,5-trimethoxyphenyl)pent-2-
enal (5)
This product was formed along with 4a in the above reaction. Prod-
uct 5 was isolated by FCC (PE–EtOAc, 7:3); yield: 85 mg (44%);
yellowish oil.
IR (CHCl3): 2938, 1681, 1588, 1506, 1456, 1420, 1328, 1236, 1123,
1005, 907, 821 cm–1.
1H NMR (500 MHz, CDCl3): d = 9.46 (s, 1 H), 6.63 (t, J = 7.0 Hz,
1 H), 6.35 (s, 2 H), 6.33 (s, 2 H), 3.81 (s, 9 H), 3.77 (s, 9 H), 3.53 (s,
2 H), 2.69–2.73 (m, 4 H).
13C NMR (125 MHz, CDCl3): d = 194.3, 154.6, 153.1, 153.0, 142.4,
136.4, 136.3, 135.9, 134.5, 105.2, 105.1, 60.64, 60.62, 55.93, 55.90,
34.6, 30.9, 29.7.
HRMS (ESI): m/z calcd for C16H21NO2 + Na (M + Na)+: 282.1470;
found: 282.1461.
1-{3-[(S)-6-Methylhept-5-en-2-yl]-1H-indol-6-yl}ethanone (4g)
23
Purified by FCC (PE–EtOAc, 8:1); mp 60–62 °C; [a]D +16
(c 0.50, CHCl3).
IR (CHCl3): 3322, 2959, 2919, 2852, 1656, 1614, 1536, 1495, 1454,
1356, 1312, 1270, 1206, 1106, 816 cm–1.
HRMS (ESI): m/z calcd for C24H30O7 + Na (M + Na)+: 453.1889;
found: 453.1909.
1H NMR (300 MHz, CDCl3): d = 8.51 (br s, 1 H), 8.07 (s, 1 H), 7.73
(dd, J = 1.2, 8.4 Hz, 1 H), 7.66 (d, J = 8.4 Hz, 1 H), 7.17 (d, J = 2.4
Hz, 1 H), 5.14 (t, J = 6.9 Hz, 1 H), 3.01 (m, 1 H), 2.66 (s, 3 H), 1.88–
2.04 (m, 2 H), 1.68–1.76 (m, 1 H), 1.60 (s, 3 H), 1.57–1.61 (m, 1 H),
1.52 (s, 3 H), 1.35 (d, J = 6.9 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 198.6, 136.0, 131.5, 131.1, 130.7,
124.5, 124.2, 123.0, 119.3, 119.0, 112.2, 37.7, 30.3, 26.8, 26.1,
25.7, 21.4, 17.6.
6-Nitro-3-pentyl-1H-indole (4b)
Purified by FCC (PE–EtOAc, 8:1); mp 114–116 °C.
IR (CHCl3): 3336, 2922, 2852, 1501, 1457, 1321, 1301, 1287, 1107,
1058, 887, 821 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.54 (br s, 1 H), 8.34 (d, J = 2.1
Hz, 1 H), 8.01 (dd, J = 2.1, 9.0 Hz, 1 H), 7.63 (d, J = 9.0 Hz, 1 H),
7.29 (s, 1 H), 2.76 (t, J = 7.2 Hz, 2 H), 1.71 (m, 2 H), 1.40–1.25 (m,
4 H), 0.91 (t, J = 6.9 Hz, 3 H).
HRMS (ESI): m/z calcd for C18H24NO (M + H)+: 270.1858; found:
270.1860.
13C NMR (75 MHz, CDCl3): d = 143.1, 134.7, 132.3, 127.2, 118.8,
118.3, 114.6, 108.0, 31.7, 29.8, 24.8, 22.5, 14.0.
Synthesis 2008, No. 24, 3981–3987 © Thieme Stuttgart · New York

3986
Z. Xu et al.
PAPER
3-(3,4,5-Trimethoxybenzyl)-6-(trifluoromethyl)-1H-indole (4h)
Purified by FCC (PE–EtOAc, 4:1); mp 138–139 °C.
IR (KBr): 3132, 3094, 3045, 2921, 2854, 2812, 1724, 1620, 1493,
1462, 1415, 1371, 1292, 1122, 1101, 897, 817, 784, 769, 727 cm–1.
IR (CHCl3): 3348, 1933, 1590, 1504, 1457, 1421, 1332, 1233, 1157,
1103, 1051, 1001, 915, 813 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.53 (br s, 1 H), 7.64 (s, 1 H), 7.61
(d, J = 8.5 Hz, 1 H), 7.33 (dd, J = 1.0, 8.5 Hz, 1 H), 7.09 (d, J = 2.0
Hz, 1 H), 6.52 (s, 2 H), 4.08 (s, 2 H), 3.85 (s, 3 H), 3.80 (s, 6 H).
13C NMR (125 MHz, CDCl3): d = 153.1, 136.5, 136.1, 135.3, 129.6,
125.2 (q, J = 271.5 Hz), 125.2, 124.0 (q, J = 31.8 Hz), 119.3, 115.9
(q, J = 3.5 Hz), 115.7, 108.7 (q, J = 4.4 Hz), 105.6, 60.8, 56.0, 31.8.
1H NMR (300 MHz, CDCl3): d = 8.87 (br s, 1 H), 8.48 (dd, J = 1.2,
4.5 Hz, 1 H), 7.63 (dd, J = 1.2, 8.1 Hz, 1 H), 7.25 (d, J = 2.7 Hz, 1
H), 7.09 (dd, J = 4.5, 8.1 Hz, 1 H), 2.87 (t, J = 7.2 Hz, 2 H), 1.76 (m,
2 H), 1.36 (m, 4 H), 0.88 (t, J = 6.9 Hz, 3 H).
13C NMR (75 MHz, CD3OD): d = 145.6, 141.9, 131.3, 127.5, 120.3,
117.2, 116.8, 32.9, 31.2, 24.8, 23.7, 14.5.
HRMS (ESI): m/z calcd for C12H17N2 (M + H)+: 189.13863; found:
189.13787.
HRMS (ESI): m/z calcd for C19H18F3NO3 + Na (M + Na)+:
388.1136; found: 388.1128.
3-Phenyl-1H-pyrrolo[3,2-b]pyridine (7b)
Purified by FCC (PE–EtOAc, 4:1); oil.
3-(3,4,5-Trimethoxybenzyl)-5-nitro-1H-indole (4i)
Purified by FCC (PE–EtOAc, 5:2); mp 167–168 °C.
1H NMR (300 MHz, CD3OD): d = 8.36 (dd, J = 1.5, 4.8 Hz, 1 H),
7.93 (dt, J = 2.0, 8.1 Hz, 2 H), 7.83 (dd, J = 1.5, 8.1 Hz, 1 H), 7.82
(s, 1 H), 7.39 (m, 2 H), 7.25–7.17 (m, 2 H).
13C NMR (125 MHz, CD3OD): d = 144.4, 143.5, 135.7, 131.7,
129.5, 128.3, 127.6, 126.9, 120.6, 117.8, 117.5.
HRMS (ESI): m/z calcd for C13H11N2 (M + H)+: 195.09168; found:
195.09231.
IR (CHCl3): 3338, 2927, 1591, 1506, 1458, 1421, 1327, 1239, 1125,
1002, 812 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.76 (br s, 1 H), 8.54 (d, J = 2.0
Hz, 1 H), 8.08 (dd, J = 2.0, 9.0 Hz, 1 H), 7.38 (d, J = 9.0 Hz, 1 H),
7.09 (s, 1 H), 6.52 (s, 2 H), 4.08 (s, 2 H), 3.84 (s, 3 H), 3.81 (s, 6 H).
13C NMR (125 MHz, CDCl3): d = 153.3, 141.6, 139.4, 136.4, 135.8,
3-Pentyl-1H-pyrrolo[2,3-c]pyridine (7c)
Purified by FCC (CH2Cl2–MeOH, 15:1); oil.
126.8, 125.4, 118.3, 117.8, 116.4, 111.1, 105.7, 60.9, 56.1, 31.7.
HRMS (ESI): m/z calcd for C18H18N2O5 + Na (M + Na)+: 365.1113;
found: 365.1097.
IR (KBr): 3141, 3091, 2956, 2924, 2854, 2766, 1615, 1501, 1459,
1219, 1123, 1037, 1025, 888, 809, 790 cm–1.
3-Phenyl-1H-indole-5-carbonitrile (4j)
Purified by FCC (PE–EtOAc, 5:1); mp 158–159 °C.
1H NMR (300 MHz, CDCl3): d = 10.93 (br s, 1 H), 8.80 (s, 1 H),
8.22 (d, J = 5.4 Hz, 1 H), 7.54 (d, J = 5.4 Hz, 1 H), 7.24 (s, 1 H),
2.74 (t, J = 7.5 Hz, 2 H), 1.70 (m, 2 H), 1.36 (m, 4 H), 1.90 (t, J = 7.2
Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 136.5, 133.9, 133.6, 132.6, 126.6,
116.3, 113.9, 31.7, 29.9, 24.7, 22.5, 14.0.
IR (CHCl3): 3287, 2221, 1600, 1544, 1468, 1450, 1427, 1359, 1265,
1246, 1113, 970, 912, 876 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.83 (br s, 1 H), 8.27 (s, 1 H), 7.61
(d, J = 7.2 Hz, 2 H), 7.46–7.52 (m, 5 H), 7.36 (t, J = 7.2 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 138.3, 134.0, 129.0, 127.5, 126.7,
125.7, 125.6, 125.1, 123.8, 120.8, 119.1, 112.4, 103.1.
HRMS (ESI): m/z calcd for C12H17N2 (M + H)+: 189.13863; found:
189.13785.
HRMS (ESI): m/z calcd for C16H14N2O + Na (M + MeOH + Na)+:
273.1004; found: 273.1009.
3-Phenyl-1H-pyrrolo[2,3-c]pyridine (7d)
Purified by FCC (CH2Cl2–MeOH, 12:1); oil.
1H NMR (300 MHz, CD3OD): d = 8.72 (s, 1 H), 8.12 (d, J = 5.4 Hz,
1 H), 7.86 (dd, J = 0.9, 5.4 Hz, 1 H), 7.79 (br s, 1 H), 7.65 (dt,
J = 1.5, 8.7 Hz, 2 H), 7.24 (dt, J = 1.5, 8.7 Hz, 2 H), 7.26 (tt, J = 1.5,
8.7 Hz, 1 H).
13C NMR (125 MHz, CD3OD): d = 138.4, 136.0, 135.6, 135.1,
131.9, 129.9, 128.7, 128.1, 127.2, 118.2, 115.6.
3-Hexyl-6-nitro-1H-indole (4k)
Purified by FCC (PE–EtOAc, 16:1); mp 102–103 °C.
IR (CHCl3): 3360, 2921, 2856, 1501, 1463, 1325, 1103, 1057, 877,
831 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.57 (br s, 1 H), 8.36 (d, J = 2.1
Hz, 1 H), 8.01 (dd, J = 2.1, 9.0 Hz, 1 H), 7.63 (d, J = 9.0 Hz, 1 H),
7.29 (d, J = 2.4 Hz, 1 H), 2.76 (t, J = 7.2 Hz, 2 H), 1.70 (m, 2 H),
1.28–1.42 (m, 6 H), 0.89 (t, J = 7.2 Hz, 3 H).
HRMS (ESI): m/z calcd for C13H11N2 (M + H)+: 195.09168; found:
195.09213.
13C NMR (75 MHz, CDCl3): d = 143.1, 134.7, 132.4, 127.3, 118.8,
5-Chloro-3-phenyl-1H-pyrrolo[2,3-b]pyridine (7e)
Purified by FCC (PE–EtOAc, 4:1); oil.
118.3, 114.6, 108.1, 31.7, 30.0, 29.2, 24.8, 22.6, 14.1.
HRMS (ESI): m/z calcd for C14H18N2O2 + Na (M + Na)+: 269.1266;
found: 269.1268.
IR (KBr): 3451, 3120, 3023, 2879, 1599, 1565, 1531, 1478, 1410,
1275, 1126, 910, 758, 699, 664 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 12.22 (s, 1 H), 8.34 (d, J = 2.1
Hz, 1 H), 8.30 (d, J = 2.1 Hz, 1 H), 8.01 (d, J = 2.7 Hz, 1 H), 7.74
(dt, J = 1.5, 8.4 Hz, 2 H), 7.46 (dt, J = 1.5, 8.4 Hz, 2 H), 7.28 (tt,
J = 1.5, 8.4 Hz, 1 H).
13C NMR (75 MHz, DMSO-d6): d = 147.4, 141.0, 134.3, 128.9,
126.6, 126.3, 126.0, 125.8, 123.0, 118.1, 114.2.
3-Pentyl-1H-pyrrolo[3,2-b]pyridine (7a); Typical Procedure
A solution of 3-amino-2-chloropyridine (6a; 39 mg, 0.3 mmol),
heptanal (103 mg, 0.9 mmol), and DABCO (101 mg, 0.9 mmol) in
anhyd DMA (1.5 mL) was degassed for 20 min. Pd(dba)2 (8.6 mg,
0.015 mmol) and t-Bu3P·HBF4 (8.7 mg, 0.03 mmol) were added,
and the resulting mixture was heated at 150 °C for 9 h. The mixture
was cooled to r.t. and diluted with H2O (15 mL). The aqueous phase
was extracted with EtOAc (2 × 15 mL). The combined organic
phases were washed with brine (3 × 15 mL), dried (Na2SO4), and
evaporated to dryness under reduced pressure. Purification of the
crude product by FCC (PE–EtOAc, 4:1) provided the desired prod-
uct 7a; yield: 25 mg (44%); oil (Table 3).
5-(Trifluoromethyl)-3-phenyl-1H-pyrrolo[2,3-b]pyridine (7f)
Purified by FCC (PE–EtOAc, 4:1); mp 209–211 °C.
IR (CHCl3): 3129, 2883, 1591, 1536, 1348, 1307, 1281, 1114, 1070,
973, 916, 902, 829 cm–1.
Synthesis 2008, No. 24, 3981–3987 © Thieme Stuttgart · New York

PAPER
Synthesis of 2-Unsubstituted Indoles and Azaindoles
3987
1H NMR (300 MHz, acetone-d6): d = 11.46 (br s, 1 H), 8.63 (d,
J = 1.8 Hz, 1 H), 8.57 (d, J = 1.8 Hz, 1 H), 8.00 (s, 1 H), 7.76 (dt,
J = 1.5, 7.5 Hz, 2 H), 7.48 (t, J = 1.5, 7.5 Hz, 2 H), 7.32 (tt, J = 1.5,
7.5 Hz, 1 H).
13C NMR (75 MHz, acetone-d6): d = 151.6, 141.0 (q, J = 3.8 Hz),
135.1, 129.9, 127.9, 127.4, 126.3, 126.2 (q, J = 271.0 Hz), 125.9 (q,
J = 3.8 Hz), 119.7 (q, J = 31.6 Hz), 117.8, 117.6.
Lautens, M. Org. Lett. 2007, 9, 2955. (g) Fang, Y.-Q.;
Lautens, M. J. Org. Chem. 2008, 73, 538. (h) Leogane, O.;
Lebel, H. Angew. Chem. Int. Ed. 2008, 47, 350. (i) Jensen,
T.; Pedersen, H.; Bang-Andersen, B.; Madsen, R.;
Jørgensen, M. Angew. Chem. Int. Ed. 2008, 47, 888.
(j) Ackermann, L.; Sandmann, R.; Villar, A.; Kaspar, L. T.
Tetrahedron 2008, 64, 769.
(6) (a) Chen, C.-Y.; Lieberman, D. R.; Larsen, R. D.;
Verhoeven, T. R.; Reider, P. J. J. Org. Chem. 1997, 62,
2676. (b) From o-chloroaniline, see: Nazaré, M.; Schneider,
C.; Lindenschmidt, A.; Will, D. W. Angew. Chem. Int. Ed.
2004, 43, 4526.
(7) (a) Jia, Y.; Zhu, J. Synlett 2005, 2469. (b) Jia, Y.; Bois-
Choussy, M.; Zhu, J. Org. Lett. 2007, 9, 2401. (c) Jia, Y.;
Bois-Choussy, M.; Zhu, J. Angew. Chem. Int. Ed. 2008, 47,
4167. (d) Velthuisen, E. J.; Danishefsky, S. J. J. Am. Chem.
Soc. 2007, 129, 10640.
(8) For reviews of palladium-catalyzed cross-coupling reactions
of aryl chlorides, see: (a) Littke, A. F.; Fu, G. C. Angew.
Chem. Int. Ed. 2002, 41, 4176. (b) Fu, G. C. J. Org. Chem.
2004, 69, 3245.
(9) (a) Jia, Y.; Zhu, J. J. Org. Chem. 2006, 71, 7826.
(b) Martín, R.; Buchwald, S. L. Angew. Chem. Int. Ed. 2007,
46, 7236.
HRMS (ESI): m/z calcd for C14H10F3N2 (M + H)+: 263.0785; found:
263.0796.
Acknowledgment
We are grateful to Peking University Health Science Center and the
National Natural Science Foundation of China (20842004) for their
generous financial support of this research. We also thank Prof.
Jieping Zhu (ICSN, Gif) for helpful discussions and generous gift
of ligands.
References
(1) For recent reviews on indole-containing natural products,
see: (a) Somei, M.; Yamada, F. Nat. Prod. Rep. 2005, 22,
73. (b) Kawasaki, T.; Higuchi, K. Nat. Prod. Rep. 2005, 22,
761. (c) Higuchi, K.; Kawasaki, T. Nat. Prod. Rep. 2007, 24,
843; and references cited therein.
(2) For recent reviews on the construction of the indole ring,
see: (a) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000,
1045. (b) Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006,
106, 2875; and references cited therein.
(3) For recent reports on indole synthesis without a palladium
catalyst, see: (a) Tokuyama, H.; Yamashita, T.; Reding, M.
T.; Kaburagi, Y.; Fukuyama, T. J. Am. Chem. Soc. 1999,
121, 3791. (b) Du, Y.; Liu, R.; Linn, G.; Zhao, K. Org. Lett.
2006, 8, 5919. (c) Liu, F.; Ma, D. J. Org. Chem. 2007, 72,
4844. (d) Yin, Y.; Ma, W.; Chai, Z.; Zhao, G. J. Org. Chem.
2007, 72, 5731. (e) Chen, Y.; Xie, X.; Ma, D. J. Org. Chem.
2007, 72, 9329. (f) Cariou, K.; Ronan, B.; Mignani, S.;
Fensterbank, L.; Malacria, M. Angew. Chem. Int. Ed. 2007,
46, 1881. (g) Trost, B. M.; McClory, A. Angew. Chem. Int.
Ed. 2007, 46, 2074. (h) Nakamura, I.; Yamagishi, U.; Song,
D.; Konta, S.; Yamamoto, Y. Angew. Chem. Int. Ed. 2007,
46, 2284. (i) Ohno, H.; Ohta, Y.; Oishi, S.; Fujii, N. Angew.
Chem. Int. Ed. 2007, 46, 2295. (j) Li, G.; Huang, X.; Zhang,
L. Angew. Chem. Int. Ed. 2008, 47, 346. (k) Alex, K.;
Tillack, A.; Schwarz, N.; Beller, M. Angew. Chem. Int. Ed.
2008, 47, 2304.
(4) For recent reviews on palladium-catalyzed synthesis of
indoles, see: (a) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005,
105, 2873. (b) Zeni, G.; Larock, R. C. Chem. Rev. 2006, 106,
4644. (c) Ackermann, L. Synlett 2007, 507.
(5) For reports on palladium-catalyzed indole synthesis, see:
(a) Mori, M.; Chiba, K.; Ban, Y. Tetrahedron Lett. 1977,
1037. (b) Larock, R. C.; Yum, E. K. J. Am. Chem. Soc. 1991,
113, 6689. (c) Larock, R. C.; Yum, E. K.; Refvik, M. D.
J. Org. Chem. 1998, 63, 7652. (d) Ragaini, F.; Rapetti, A.;
Visentin, E.; Monzani, M.; Caselli, A.; Cenini, S. J. Org.
Chem. 2006, 71, 3748. (e) Zhao, J.; Larock, R. C. J. Org.
Chem. 2006, 71, 5340. (f) Nagamochi, M.; Fang, Y.-Q.;
(10) (a) Gooßen, L. J.; Ferwanah, A.-R. S. Synlett 2000, 1801.
(b) Yamanoi, Y. J. Org. Chem. 2005, 70, 9607.
(c) McNeill, E.; Barder, T. E.; Buchwald, S. L. Org. Lett.
2007, 9, 3785. (d) Solé, D.; Serrano, O. J. Org. Chem. 2008,
73, 2476.
(11) Reaction of o-chloroaniline with phenylacetaldehyde (1.0
equiv or 3.0 equiv) gave the expected indole in 55 and 70%
yield, respectively. Reaction of 2-chloro-5-methoxyaniline
with methyl (S)-2-N,N-di-tert-butoxycarbonyl-5-oxo-
pentanoate (1.0 equiv or 3.0 equiv) gave the 6-methoxy-
tryptophan derivative in 21 and 25% yield, respectively.
Reaction of 2-chloro-5-methylaniline with phenylacet-
aldehyde (1.0 equiv or 3.0 equiv) gave the 5-methyl-3-
phenyl-1H-indole in 56 and 67% yield, respectively.
1H NMR (300 MHz, CDCl3): d = 8.08 (br s, 1 H), 7.77 (s, 1
H), 7.70 (dd, J = 1.2, 7.4 Hz, 2 H), 7.49 (t, J = 7.4 Hz, 2 H),
7.35–7.31 (m, 3 H), 7.10 (d, J = 8.4 Hz, 1 H), 2.52 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 135.7, 134.9, 129.6, 128.7,
127.5, 125.9, 125.8, 124.0, 121.9, 119.4, 117.8, 111.0, 21.6.
(12) For recent reviews on azaindole synthesis, see:
(a) Popowycz, F.; Routier, S.; Joseph, B.; Mérour, J.-Y.
Tetrahedron 2007, 63, 1031. (b) Popowycz, F.; Mérour,
J.-Y.; Joseph, B. Tetrahedron 2007, 63, 8689. (c) Song,
J. J.; Reeves, J. T.; Gallou, F.; Tan, Z.; Yee, N. K.;
Senanayake, C. H. Chem. Soc. Rev. 2007, 36, 1120.
(13) For recent reports on azaindole synthesis, see:
(a) McLaughlin, M.; Palucki, M.; Davies, I. W. Org. Lett.
2006, 8, 3307. (b) Zheng, X.; Kerr, M. A. Org. Lett. 2006, 8,
3777. (c) Schirok, H. J. Org. Chem. 2006, 71, 5538.
(d) Fang, Y.-Q.; Yuen, J.; Lautens, M. J. Org. Chem. 2007,
72, 5152.
(14) (a) Roberts, B. A.; Strauss, C. R. Acc. Chem. Res. 2005, 38,
653. (b) Lachance, N.; April, M.; Joly, M.-A. Synthesis
2005, 2571.
Synthesis 2008, No. 24, 3981–3987 © Thieme Stuttgart · New York