Domino ligand-free copper-catalyzed synthesis of polysubstituted indoles

Article abstract of DOI:10.1055/s-0030-1259548

The synthesis of polysubstituted indoles is described by the domino reaction of 2-haloanilines and 1,3-dicarbonyl compounds, 1,3-diketones, β-keto esters and β-keto amides, using copper catalysis under ligand-free conditions. The protocol provides a simpl

Full text of DOI:10.1055/s-0030-1259548

LETTER
623
Domino Ligand-Free Copper-Catalyzed Synthesis of Polysubstituted Indoles
Domino
Ligand-Free
C
d
opper-Catalyzed
S
A
ynthesis of Polysu
s
bstituted
I
h
ndoles if Ali, Tharmalingam Punniyamurthy*
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781039, India
Fax +91(361)2690762; E-mail: tpunni@iitg.ernet.in
Received 24 September 2010
nyl compounds is one of the attractive processes due to the
Abstract: The synthesis of polysubstituted indoles is described by
the domino reaction of 2-haloanilines and 1,3-dicarbonyl com-
pounds, 1,3-diketones, b-keto esters and b-keto amides, using cop-
per catalysis under ligand-free conditions. The protocol provides a
availability of a range of starting materials.9,10 CuI–
BINOL has been found to be effective for the reaction of
2-iodoanilines with b-ketoesters,9a while CuI–proline has
simple, general and atom economical process for the synthesis of been used for the reactions of 2-iodotrifluoroacetanilides
with b-keto esters as well as b-keto amides.9b,c These
substituted indoles at moderate temperature.
reactions involve intermolecular C–C cross-coupling fol-
lowed by condensation of the amine with the carbonyl
group to give the indoles.9b,c
Key words: Cu2O, indoles, cesium carbonate, 1,3-dicarbonyl com-
pounds, 2-haloanilines
The use of copper oxide as an active catalyst for the cross-
coupling reactions has been demonstrated in recent
years.11,12 Since copper oxides are cheap, less toxic, readi-
Indoles are probably the most common heterocycles
found in nature1 and have been referred to as ‘privileged
structures’ of medicinal importance due to their high bind-
ing affinity with many receptors (Figure 1).2 Indoles are
also known as important structural constituent for the de-
velopment of agrochemicals,3 materials4 and perfumes.5
The development of simple, general and especially regio-
selective synthetic methods for the construction of substi-
tuted indole scaffold thus continues to be of tremendous
interest in organic synthesis.6
Table 1 Optimization of Reaction Conditionsa
O
O
OMe
I
Cu2O
OMe
+
base, solvent
100 °C, N2, 7 h
NH2
N
H
O
1a
OMe
Entry Solvent
Base
Yield (%)b
60
O
H
OMe
OMe
N
1
2
DMSO
DMF
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
KOH
O
45
N
H
MeO
H
H
OMe
3
toluene
20
MeO2C
N
N
reserpine
4
1,4-dioxane
32
O
5
i-PrOH
25
O
6
DMSO–i-PrOH (1:1)
DMSO–H2O (1:1)
DMSO–H2O (3:1)
DMSO–H2O (3:1)
DMSO–H2O (3:1)
DMSO–H2O (3:1)
DMSO–H2O (3:1)
DMSO–H2O (3:1)
DMSO–H2O (3:1)
23
N
Me
ondansetron
7
51
OH
H
O
8
81
H
N
OH
9
42
H
O
10
11
12
13
14
33
lolicine A
K3PO4
Cs2CO3
Cs2CO3
Cs2CO3
18
Figure 1 Examples of biologically active and naturally occurring
compounds
48c
54d
n.d.e
2,3-Disubstituted indole substructures are widely distrib-
uted in nature as indole alkaloids and drugs.7 Among the
studies developed for their synthesis,8,9 the copper-cata-
lyzed domino reaction of 2-iodoaniline with 1,3-dicarbo-
a Cu2O (10 mol%), 2-iodoaniline (1 mmol), base (1 mmol) and methyl
acetoacetate (1.2 mmol) were stirred at 100 °C for 7 h in solvent.
b Isolated yield.
c Temperature: 80 °C.
SYNLETT 2011, No. 5, pp 0623–0626
Advanced online publication: 11.02.2011
x
x.
x
x.
2
0
1
1
d A 5 mol% amount of Cu2O was used.
e Cu2O was not used.
DOI: 10.1055/s-0030-1259548; Art ID: D26210ST
© Georg Thieme Verlag Stuttgart · New York

624
Md A. Ali, T. Punniyamurthy
LETTER
ly available and provide simplified product isolation, their 1,4-dioxane and 2-propanol as the solvent afforded 1a in
further application to organic synthesis warrants investi- 25–61% conversion. Either lowering or increasing the
gation. Herein, we report the synthesis of polysubstituted DMSO to water ratio led to 1a in 51% conversion. In the
indoles by Cu2O-catalyzed domino reaction of 2-haloa- screened set of bases (K2CO3, KOH, K3PO4 and Cs2CO3),
nilines with a series of 1,3-dicarbonyl compounds, 1,3- Cs2CO3 was found to be superior to others affording the
diketone, b-keto ester and b-keto amide, in a 3:1 mixture best results. Replacing Cs2CO3 with K2CO3, KOH and
of DMSO–water at moderate temperature. The procedure K3PO4 as the base provided 1a in 18–42% conversion.
is simple, general, ligand-free and atom-economical for Lowering the reaction temperature (80 °C) or the catalyst
the synthesis of polysubstituted indoles.
loading to 5 mol% led to production of 1a in 48% and
54% yield, respectively. A control experiment confirmed
that, without the copper reagent, no indole formation oc-
curred.
First, the optimization of the reaction conditions was car-
ried out with 2-iodoaniline and methyl acetoacetate as the
model substrates (Table 1). The reaction occurred
smoothly to afford the desired 2,3-disubstituted indole 1a Next, the scope of the procedure was studied for other
in 81% conversion when the substrates were stirred with substrates (Scheme 1). The reactions of 2-iodoanilines
10 mol% of Cu2O and one equivalent of Cs2CO3 for seven having 4-chloro, 4-nitro, 4-methyl, 4,5-dimethyl and 4,6-
hours at 100 °C in a 3:1 mixture of DMSO and water un- dimethyl substituents were investigated with 1,3-dicarbo-
der a nitrogen atmosphere. Using DMSO, DMF, toluene, nyl compounds, pentane-2,5-dione, 5,5-dimethylcyclo-
O
R3
O
R1 = H, Cl, Me, NO2
I
Cu2O (10 mol%)
Cs2CO3 (1 equiv)
R3
R2
2 = Me, Ph
3 = Me, OMe, NHAr
+
R
R
DMSO–H2O (3:1)
N2, 100 °C
R1
N
R1
NH2
H
R2–R3 = CH2C(Me)2CH2
O
R2
1a–s
O
O
O
O
O
OMe
OMe
OMe
OMe
OMe
Cl
N
N
H
1d
N
H
N
N
H
H
H
1a
1b
1c
1e
(7 h, 80%)
(12 h, 83%)
(7 h, 81%)
O
(10 h, 81%)
(9 h, 78%)
O
O
O
O
OEt
Ph
OEt
Cl
N
H
N
H
N
H
N
N
H
H
1g
1h
1f
1i
1j
(10 h, 76%)
(9 h, 87%)
(12 h, 69%)
(7 h, 84%)
(9 h, 90%)
O
O
O
O
O
NH
O2N
N
N
N
N
N
H
H
H
H
H
1m
1n
1o
(9 h, 91%)
1k
1l
(10 h, 82%)
(8 h, 85%)
(12 h, 66%)
(9 h, 88%)
O
O
O
O
NH
NH
NH
NH
O2N
Cl
N
N
N
H
N
H
H
H
1p
1q
1r
1s
(10 h, 82%)
(10 h, 90%)
(12 h, 62%)
(10 h, 89%)
Scheme 1 Reaction of 1,3-dicarbonyl compounds with substituted aryl iodides. Reagents and conditions: Cu2O (10 mol%), 2-iodoaniline
(1 mmol), Cs2CO3 (1 mmol) and 1,3-diketone or b-ketoester or b-ketoamide (1.2 mmol) were stirred at 100 °C in a DMSO–H2O mixture (3:1,
1 mL) under a nitrogen atmosphere. Isolated yields are shown.
Synlett 2011, No. 5, 623–626 © Thieme Stuttgart · New York

LETTER
Domino Ligand-Free Copper-Catalyzed Synthesis of Polysubstituted Indoles
625
O
hexane-1,3-dione, ethyl acetoacetate, methyl acetoacetate
and 3-oxo-N-p-tolylbutanamide. All the substrates readily
participated in reaction to give the corresponding
polysubstituted indoles 1b–s in 7–12 hours with 62–91%
yield. The reactions were selective and no by-product was
obtained. These results clearly suggest that the protocol is
simple and general for the regiospecific synthesis of
polysubstituted indoles in high yield.
O
X
R2
R2
+
R1
O
N
H
NH2
O
R1
condensation
X
O
R2
R2
N
R1
N
R1
O
O
CuI
OMe
a
Br
Cu2O (10 mol%)
Cs2CO3 (1 equiv)
+
OMe
reductive
oxidative
addition
elimination
DMSO–H2O (3:1)
N2, 120 °C
NH2
R
O
X
CuIII
O
N
O
R
H
R = H, Me
CuIII
R2
R2
O
O
O
OMe
OMe
X = Br, I
OMe
R1
N
R1
R1 = alkyl, aryl
N
d
b
R2 = alkyl, alkoxy, NHAr
N
N
N
H
X
O
H
H
CuIII
Cs2CO3
R2
1e
(12 h, 39%)
1a
(10 h, 27%)
1d
CsX
(12 h, 41%)
N
R1
c
Scheme 2 Reactions of 2-bromoanilines and methyl acetoacetate.
Reagents and conditions: Cu2O (10 mol%), 2-bromoaniline (1 mmol),
Cs2CO3 (1 mmol), and methyl acetoacetate (1.2 mmol) were stirred at
120 °C in a DMSO–H2O mixture (3:1, 1 mL) under a nitrogen at-
mosphere. Isolated yields are shown.
Scheme 3 The possible mechanistic pathway
regiospecific synthesis of polysubstituted indoles in high
yield.
Finally, the reactions of 2-bromoanilines with methyl ac-
etoacetate were studied (Scheme 2). These reactions re-
quired slightly higher temperature to afford the products
in 27–41% yield. Thus, 2-bromoaniline underwent reac-
tion at 120 °C in 10 hours to give 1a in 27% yield. Like-
wise, 2-bromoaniline having 4,5-dimethyl and 4,6-
dimethyl substituents provided the respective substituted
indoles 1d and 1e in 12 hours with 41% and 39% yield, re-
spectively.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
We thank the Department of Science and Technology, New Delhi
and the Council of Scientific and Industrial Research, New Delhi,
for financial support.
The proposed catalytic cycle is shown in Scheme 3. The
reaction of iodobenzene with methyl acetoacetate was in-
vestigated using 10 mol% of Cu2O and no intermolecular
C–C cross-coupling was observed. On the other hand,
aniline readily underwent condensation with methyl ace-
toacetate to give the imine derivative in quantitative yield.
These results suggest that the present protocol involves
condensation followed by intramolecular C–C cross-cou-
pling to afford the indoles. Thus, the condensation of 2-
haloaniline with carbonyl compound can give imine de-
rivative a that might undergo oxidative addition with
Cu(I) to give the intermediate b. The latter with base
could generate intermediate c which may transform into d
by nucleophilic substitution. The intermediate d could
complete the catalytic cycle by reductive elimination to
generate the indole.
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Md A. Ali, T. Punniyamurthy
LETTER
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