A Mild Approach for the Synthesis of Indoles from N -(2-Iodo-aryl)formAamides and Phenylacetylene by a Copper(I)- and Palladium-Catalyzed Cascade Process

Article abstract of DOI:10.1055/s-0034-1378899

An efficient one-pot copper(I)- and palladium-catalyzed synthesis of indoles from N-(2-iodo-aryl)formamides and phenylAacetylene is described. The cascade reaction comprises a Sonogashira cross-coupling, an intramolecular C-N bond formation, and hydrolysi

Full text of DOI:10.1055/s-0034-1378899

LETTER
▌2455
lAetteMr ild Approach for the Synthesis of Indoles from N-(2-Iodo-aryl)form-
amides and Phenylacetylene by a Copper(I)- and Palladium-Catalyzed
Cascade Process
Indoles from N-(2-Iodo-aryl)formamides and Phenylacetylene
Atiur Ahmed, Munmun Ghosh, Shubhendu Dhara, Jayanta K. Ray*
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India
Fax +91(3222)282252; E-mail: jkray@chem.iitkgp.ernet.in
Received: 03.07.2014; Accepted after revision: 06.08.2014
Me
O
Abstract: An efficient one-pot copper(I)- and palladium-catalyzed
H
S
NH
N
synthesis of indoles from N-(2-iodo-aryl)formamides and phenyl-
acetylene is described. The cascade reaction comprises a Sonogas-
hira cross-coupling, an intramolecular C–N bond formation, and
hydrolysis of the intermediate indole-1-carbaldehyde promoted by
the same catalyst and base systems.
O
O
N
N
N
N
Me
ramosetron
N
N
HN
H
Key words: indole, cascade reaction, copper(I) and palladium cat-
alyst, N-(2-iodo-aryl)formamide, hydrolysis
F
O
delavirdine
HO
The indole moiety is present as a structural scaffold in a
large number of natural products and pharmaceuticals
(Figure 1).1–3 Indolyl alkaloids, such as reserpine, have
been developed as therapeutics for the treatment of central
nervous system and cardiovascular system related diseas-
es.4 Vincristine and tryprostatins A and B are antimitotic
agents that have been clinically used for cancer chemo-
therapy.4a,5 Indole derivatives have also been found to ex-
N
OH
N
OH
CO2H
O
OH
fluvastatin
N
bazedoxifene
hibit
anti-inflammatory,6
antidepressive,3
antihypertensive,7 and antiosteoporotic activity.8 In addi-
tion, more than 4000 natural products have been identified
containing an indole nucleus and have found diverse uses
such as molecular probes or pharmacological tools.1,9
Figure 1 Pharmaceutical agents with indole scafford
previous work:
H
In recent years, transition metals, in particular palladium-
catalyzed reactions, have been employed to afford in-
doles,10 as well as solid-phase methodologies,11 multi-
components processes,12 and microwave-assisted
reactions.13
I
10% Pd/C
R
+
ZnCl2
N
NHTs
R
Ts
present work:
Recently, we described a straightforward synthetic meth-
od for the preparation of the indole skeleton through si-
multaneous C–C/C–N bond formation. The reaction was
accelerated by ZnCl2 hydrate and a Pd/C catalyst (Scheme
1, top).14 In this current work (Scheme 1, bottom), we
have observed that changing the protecting group from to-
syl to carbaldehyde resulted in a cascade leading to in-
doles unsubstituted on nitrogen with the CHO group
acting as a labile group under experimental conditions.
I
H
Pd catalyst
Cu(I)
R
+
R
Ph
NH
N
H
CHO
Ph
Scheme 1 Synthesis of 2-substituted indoles
In this regard N-(2-iodo-aryl)formamides 4 were synthe-
sized from the corresponding o-iodoanilines using a Vils-
meier–Haack approach (Scheme 3).16 In the first instance,
we examined the synthesis of 5-methyl-2-phenyl-1H-in-
dole (5a) starting from formamide 4a and commercially
available phenylacetylene (2, Scheme 4) in the presence
of catalytic amounts of CuI, Pd(PPh3)4, and Et3N as base,
when the expected indole 5a was produced in 80% yield
within 1.5 hours at 110 °C in DMF solvent (Table 1, entry
1).
Our initial efforts at obtaining indoles directly from 4-
methyl-2-iodoaniline (1a) and phenylacetylene (2) under
Sonogashira cross-coupling15 conditions failed (Scheme
2). Next, we turned our attention to afford indoles from
anilines having a derivatized NH2 group.
SYNLETT 210014, 2517, 2455–2458
Advanced online publication: 08.09.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0034-1378899; Art ID: st-2014-d0566-l
© Georg Thieme Verlag Stuttgart · New York

2456
A. Ahmed et al.
LETTER
CuI (10 mol%)
Pd(OAc)2 (5 mol%)
Ph3P (25 mol%)
2 (1.010 mmol)
CuI, Pd(PPh3)4
I
H
Ph
I
N
Et3N, DMF
110 °C, 1.5 h
80%
NH
+
H
Et3N (7 equiv), DMF
90–100 °C
3 h
CHO
4a
(1 mmol)
NH2
Ph
5a
NH2
1a
(1 mmol)
2
3a 75%
Scheme 4 Synthesis of indole from formamide
(1.01 mmol)
Scheme 2 Sonogashira cross-coupling
In order to optimize reaction conditions, we employed an
array of catalytic systems, bases, ligands, and solvents as
presented in Table 1. When the synthesis was performed
using Pd(OAc)2 catalyst in place of other palladium sourc-
es by fixing CuI as cocatalyst the corresponding indole
was obtained in better yields (Table 1, entries 1–4). How-
ever, the product yield decreased on changing the cocata-
lyst from CuI to CuBr (Table 1, entries 5 and 11) while
maintaining the same palladium source. The reaction was
also influenced by ligands and more so by the base, with
Br3P (2.7 mmol)
I
I
DMF (3.0 mmol)
R
R
CHCl3 (0.80 mL)
0 °C to r.t., 1–2 h
NH2
NH
CHO
1a
(1 mmol)
4
88–92%
Scheme 3 N-Formylation of o-iodoanilines
Table 1 Optimization of the Reaction Conditions
2
I
Pd catalyst
Ph
N
CuX, base
ligand, solvent
110 °C, 1.5 h
NH
H
CHO
4a
5a
Entry
Catalyst
Cocatalyst
Ligand
Base (equiv)
Solvent
Yield (%)a
1
2
Pd(PPh3)4
Pd(PPh3)2Cl2
PdCl2
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuBr
CuI
CuI
CuI
CuI
CuI
CuI
CuI
ZnCl2
Et3N (7)
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
80
82
80
89
94
90
86
80
76
85
71
82
70
68
71
69
72
70
83
Et3N (7)
3
Ph3P
Ph3P
PCy3
PCy3
PCy3
PCy3
PCy3
dppp
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
Ph3P
Et3N (7)
4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd/C
Et3N (7)
5
Et3N (7)
6
Et3N (7)
7
Et3N (7)
8
Et3N (7)
9
Et3N (7)
10
11
12
13
14
15
16
17
18
19
Et3N (7)
Et3N (7)
i-Pr2NEt (7)
K2CO3 (7)
Cs2CO3 (7)
Na2CO3 (7)
Li2CO3 (7)
NaOAc (7)
KOAc (7)
Et3N (7)
a Isolated yields after purification by column chromatography.
Synlett 2014, 25, 2455–2458
© Georg Thieme Verlag Stuttgart · New York

LETTER
Indoles from N-(2-Iodo-aryl)formamides and Phenylacetylene
2457
To examine the scope of this methodology, the reaction of
several formamides 4 obtained from various o-iodoani-
lines with phenylacetylene (2) was carried out under the
above optimized conditions; the results of which are sum-
marized in Table 2. The cases in which the formamides
contained electron-donating groups (4a,b) and weak elec-
tron-withdrawing groups (4c), the reactions were com-
plete in short time (<1.5 h), and the corresponding indoles
5 were produced in high yields (Table 2, entries 1–3). The
yields of the indoles were found to decrease with strong
electron-withdrawing groups on formamides, and com-
paratively long reaction times were required for the reac-
tions to be complete (Table 2, entries 4–7).
Table 2 Copper–Palladium-Catalyzed Synthesis of Indoles by C–
C/C–N Bond Formations
H
CuI (10 mol%)
Pd(OAc)2 (5 mol%)
I
R
R
+
Ph
NH
Cy3P (25 mol%)
Et3N, DMF
110 °C
N
H
Ph
CHO
4
2
5
Entry Formamide 4
Time Product 5
(h)
Yield
(%)a
I
Ph
Ph
CHO
CHO
1
1.5
94
92
N
H
N
H
These observations lead us to assume that the reaction
proceeds through a sequence of Sonogashira cross-cou-
pling, followed by intramolecular C–N bond formation
catalyzed by the same catalyst system, leading to forma-
tion of intermediate substance 7, which on hydrolysis af-
fords 517 (Scheme 5).
5a
4a
I
N
H
N
2
1.5
H
5b
4b
Br
Ph
H
I
Br
I
CuI
Ph
CHO
CHO
CHO
+
N
H
3
4
5
6
7
N
H
1.5
89
83
78
79
75
NH
Pd(OAc)2
hydrolysis
NH
Ph
2
CHO
CHO
5c
4c
Cl
4a
6
I
Cl
Ph
Ph
N
H
2.5
N
H
Ph
CHO
Ph
N
N
H
5d
4d
Cl
5a
7
I
Cl
Scheme 5 Mechanism proposed for indole synthesis
N
H
3
Cl
N
H
Cl
In conclusion we have described an approach for the con-
struction of indoles from formamides obtained from read-
ily accessible anilines. The overall high yields, mild
reaction conditions, and the easy functionalization of the
NH2 group to NHCHO, which undergoes deprotection un-
der the reaction conditions, offers a practical means of in-
dole synthesis.
5e
4e
F
I
F
Ph
CHO
N
3
N
H
H
5f
4f
O2N
I
O2N
Ph
CHO
N
N
3
H
Acknowledgment
H
5g
A.A. thanks UGC, New Delhi for a Fellowship and also CSIR and
DST (New Delhi) for financial support.
4g
a Isolated yields after purification by column chromatography.
Supporting Information for this article is available online
at
http://www.thieme-connect.com/products/ejournals/journal/
the best yield being achieved when 4a (1.0 mmol) was
treated with 2 (1.01 mmol) in the presence of Pd(OAc)2 (5
mol%), CuI (10 mol%), Et3N (7 equiv), and PCy3 (0.25
mmol) in DMF (5 mL) at 110 °C (Table 1, entry 5).
10.1055/s-00000083.SunogIpimrfiantoSuIpg
n
fonirtat
ori
References and Notes
We also applied the optimal reaction conditions as dis-
closed in our previous report,14 but these conditions af-
forded 5a less efficiently (Table 1, entry19). Again the
absence of a cocatalyst resulted in diyne formation via ho-
mocoupling with almost all the starting material 4a re-
maining.
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 2455–2458

2458
A. Ahmed et al.
LETTER
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(17) General Procedure for the Synthesis of Indoles 5
To a DMF (5 mL) solution of a mixture of 4 (1 mmol),
phenylacetylene (2, 1.010 mmol), and PCy3 (0.25 mmol) in
a two-necked round-bottomed flask fitted with condenser,
Et3N (7 equiv), Pd(OAc)2 (5 mol%), and CuI (10 mol%)
were added, and the reaction mixture was allowed to stir at
110 °C under argon atmosphere. The progress of the reaction
was monitored by TLC. Upon completion of the reaction, the
mixture was allowed to cool to r.t, diluted with H2O and
extracted with EtOAc (3 × 20 mL). The combined organic
layers we dried over Na2SO4, filtered, and concentrated in
vacuum to furnish the crude product which was then purified
by column chromatography using silica gel (60–120 mesh)
and PE–EtOAc (10:1) as eluent.
5-Methyl-2-phenyl-1H-indole (5a)
White solid; mp 210–211 °C. 1H NMR (200 MHz, CDCl3):
δ = 8.11 (s, 1 H), 7.56–7.52 (m, 2 H), 7.36–7.14 (m, 5 H),
6.93(d, J = 8.2 Hz, 1 H), 6.65(d, J = 1.4 Hz, 1 H), 2.36 (s, 3
H). 13C NMR (50 MHz, CDCl3): δ = 138.1, 135.3, 132.7,
129.7, 129.6, 129.2, 127.8, 125.2, 124.2, 120.5, 110.8, 99.7,
21.7. Anal. Calcd (%) for C15H13N: C, 86.92; H, 6.32; N,
6.76. Found: C, 86.84; H, 6.41; N, 6.70
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Synlett 2014, 25, 2455–2458
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