Synthesis of new indolylpyrrole derivatives via a four-component domino reaction between arylglyoxals, acetylacetone, indole and aliphatic amines in aqueous media

Article abstract of DOI:10.1016/j.tetlet.2018.06.043

A novel synthesis of indolylpyrrole derivatives is described by a four-component domino reaction between arylglyoxals, acetylacetone, indole and aliphatic amines in water as solvent at 60 °C without using any catalyst or promoter. The FT-IR, ¹H NMR, ¹³C NMR spectral and elemental analysis confirm the structures of the products.

Full text of DOI:10.1016/j.tetlet.2018.06.043

Accepted Manuscript
Synthesis of New Indolylpyrrole Derivatives Via a Four-Component Domino
Reaction Between Arylglyoxals, Acetylacetone, Indole and Aliphatic Amines
in Aqueous Media
Fereshteh Mousavizadeh, Mahdiyeh Talebizadeh, Mohammad Anary-
Abbasinejad
PII:
S0040-4039(18)30797-4
https://doi.org/10.1016/j.tetlet.2018.06.043
TETL 50081
DOI:
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
24 May 2018
14 June 2018
16 June 2018
Please cite this article as: Mousavizadeh, F., Talebizadeh, M., Anary-Abbasinejad, M., Synthesis of New
Indolylpyrrole Derivatives Via a Four-Component Domino Reaction Between Arylglyoxals, Acetylacetone, Indole
and Aliphatic Amines in Aqueous Media, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.
2
018.06.043
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Synthesis of New Indolylpyrrole Derivatives Via a Four-Component Domino
Reaction Between Arylglyoxals, Acetylacetone, Indole and Aliphatic Amines in
Aqueous Media
Fereshteh Mousavizadeh, Mahdiyeh Talebizadeh, Mohammad Anary-Abbasinejad*
Department of chemistry, Vali-e-Asr University, Rafsanjan, 77176, Iran
Corresponding Author E-mail: m.anary@vru.ac.ir
H
N
O
O
O
O
OH
CH3
CH3
H O
2
2
+
+
+
R NH2
o
OH
N
1h, 60 C
R1
H
N
2
R
R2
1
R = C H CH NH 4-OCH C H
3 6 5
CH CH , 4-OCH C H CH ,
6
5
2
2,
R = OCH ,Cl, H, Br, NO
3
2
5a-i
2
2
3
6
5
2
ABSTRACT: A novel synthesis of indolylpyrrole derivatives is described by a four-component domino
o
reaction between arylglyoxals, acetylacetone, indole and aliphatic amines in water as solvent at 60 C
1
13
without using any catalyst or promoter. The FT-IR, H NMR, C NMR spectral and elemental analysis
confirm the structures of the products.
Keywords. Indolylpyrrole, Four-component reaction, Arylglyoxal, Aqueus media, Synthesis
Pyrrole ring is one of the most important chemical subunits which is widely found in the structure of many
1
therapeutically active compounds. Pyrrole ring also exists in the structure of a wide variety of natural
2
products such as vitamin B12, pigments like bilirubine and biliverdine and the porphyrine of heme. Access
to pyrrole derivatives using multi-component reactions is particularly attractive from the synthetic
3
efficiency and environmentally point of views.
Indole derivatives having a heterocyclic ring at C3 have recently attracted much attention from synthetic
4
point of view for their presence at natural products such as martefagin A6 and alkaloids, which are potent
5
-9
inhibitors of HIV-1 integrase. Some indole derivatives containing a pyrrole substituent at their C3
1
0-12
position have been recently synthesized and proven to possess interesting biological activities.
Multi-component domino reactions (MDRs), particularly those performed in water have attracted much
attraction from chemists for their synthetic power point of view and green characteristics. These reactions
have been successfully utilized for synthesis of a wide variety of chemically and biologically important
1
3
compounds.
Arylglyoxals have gained much attention for synthesis of heterocycles using multi-component reactions.
The application of arylglyoxals for preparation of a wide range of three- to six-membered heterocycles has
1
4
been recently reviewed. In continuation of our previous studies on the application of arylglyoxals in
1
5-17
synthesis of heterocyclic compounds,
we report herein a green MDR approach for synthesis of some
indole derivatives having a pyrrole functionality at their 3-position. Thus the four-component domino

2
Tetrahedron
reaction between arylglyoxals, acetylacetone, indole and aliphatic amines in water as solvent in the
absence of any catalyst or promoter afforded indole derivatives in excellent yields (Scheme 1).
Scheme 1
Table 1.
Entry
Ar
Indole
RNH
2
Product
Yield%
O
HN
CH3
CH3
1
4-ClC
6
H
4
98
N
Cl
5
a
O
HN
CH3
2
4-OCH
3
C
6
H
4
93
CH3
N
H CO
3
5b
3
4-BrC
6
H
4
93
4
4-ClC
6
H
4
94

5
4-BrC
6
H
4
95
6
4-BrC
6
H
4
93
7
4- NO
2
C
6
H
4
91
8
4-NO
2
C
6
H
4
95
9
C
6
H
5
94
At the beginning of our investigation, we carried out the reaction between 4-chlorophenylglyoxal
o
monohydrate, acetylacetone, indole and benzylamine in water as solvent. After stirring for 1h at 60 C, the
analysis of the reaction mixture by TLC showed the presence of only one product. Filtering the reaction
mixture and simple washing of the product by diethyl ether afforded the indolylpyrrole derivative 5a in
nearly quantitative yield. The NMR, IR spectral, and combustion analytical data deduced the structure of
1
product. The H NMR spectrum of compound 5a showed three sharp single signals at 1.7, 2.4 and 5.1 ppm
which are related to two methyl and one methylene groups, respectively. The aromatic protons resonated
1
3
between 6.8 and 7.3 ppm. The NH proton was observed at 10.9 ppm. The C NMR spectrum of 5a

4
Tetrahedron
exhibited twenty-four distinct signals in agreement with the proposed structure, the carbonyl carbon
resonated at 196.8 ppm. The proposed structure was also confirmed by the IR spectrum of 5a, which
-1
-1
showed the absorption bands at 1635 cm for carbonyl group and at 3359cm for NH bond.
To define the scope and generality of the reaction, a series of substituted arylglyoxals and aliphatic amines
were examined. To our delight, in each case the desired indolylpyrrole derivative was obtained in excellent
yield. This method has some advantages, as the starting materials are simply available, the reaction
conditions are simply accessible and the products were isolated in high yields by simple filtration and
washing with diethyl ether.
When the aromatic amines such as aniline or 4-methoxyaniline were used as the amine component,
complex mixtures were obtained and no pure product could be isolated. Similarly, no product could be
isolated when cyclic diketones like dimedone or ketoesters such as ethyl acetoacetate were used instead of
acetylacetone.
A plausible mechanism for the formation of compounds 5 is shown in Scheme 2. The Knovenagel
condensation of arylglyoxal and acetylacetone afforded enone 6 which under the Michael addition of indole
converted to trione derivative 7. The reaction of benzyl amine with intermediate 7, known as Paal-Knorr
pyrrole synthesis, afforded the indolylpyrrole derivative 5.
O
O
O
O
O
N
O
O
O
H
Ar
OH
OH
3
RNH2
Ar
+
5
O
Ar
-2H O
2
NH
1
2
6
7
Scheme 2
Continuing the process of our study, we decided to investigate the possibility of using the reaction
conditions for preparing and isolating intermediate 7. Thus, the reaction of arylglyoxals, acetylacetone and
o
indole was carried out in water at 60 C in the absence of any catalyst or promoter. As shown in Scheme 3
and Table 2 the indolyltrione derivatives 7a-g were obtained in excellent yields. As shown in Table 1 the
reaction is compatible for different arylglyoxals with electron deficient or electron poor aromatic rings.
Compounds 7a-g were also isolated by simple filtering the product and washing with diethyl ether. The
structures of compounds 7a-g were proved by NMR and IR spectral and analytical data. For example, the
1
H NMR spectrum of 7a showed two single signals at 1.1 and 2.2 ppm for methyl groups. Two methine
3
protons were observed as two double signals ( JHH = 11 H
Z
) at 5.0 and 5.6 ppm. The aromatic protons
1
3
resonated between 6.9-7.9 ppm and the NH proton was observed at 11.1 ppm. C NMR spectrum of 7a
exhibited nineteen distinct signals in agreement with the proposed structure, the carbonyl carbons resonated

at 196.58, 202.91 and 204.08 ppm. The proposed structure was also confirmed by the IR spectrum of 7a,
-1
which showed the absorption bands at 1725, 1700, 1678 cm for carbonyl bonds and at 3396 for NH bond.
To prove that indolyltrione derivative 7 is an intermediate for formation of indolylpyrrole derivatives 5, the
o
reaction of 7a with benzyl amine was carried out at in water at 60 C and the indolylpyrrole derivative 5a
was obtained in nearly quantitative yield.
Scheme 3
Table 2.
Entery Ar
Indole
Intermediate product
Yield%
O
O
Br
CH3
CH3
1
4-BrC
H
6 4
92
O
N
H
7
a
2
4-ClC
H
6 4
93
3
4
4-MeC
6
H
4
95
95
2
4-NO C
6
H
4

6
Tetrahedron
5
6
4-BrC
H
6 4
93
94
C
H
6 5
7
2-naphthyl
93
ASSOCIATED CONTENT
Supporting Information
1
13
Experimental procedures, H, C, NMR characterization data of all novel products (PDF)
AUTHOR INFORMATION
Corresponding Author
Corresponding Author E-mail: m.anary@vru.ac.ir
Present Addresses
Department of Chemistry, Faculty of Science, Vali-e-Asr University of Rafsanjan, Rafsanjan 77176, Iran
ACKNOWLEDGMENT
We gratefully acknowledge, the Vail-e-Asr University of Rafsanjan Faculty Research Grant for financial
support
Conclusion
In conclusion, we have achieved the synthesis of indolylpyrrole derivatives by a four-component domino
reaction between readily accessible starting materials in excellent yield. This synthesis has the advantages
that the reactions were carried out in water as solvent without using any catalyst or promoter and products
were purified by simple filtration and washing with diethyl ether.
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8
Tetrahedron
Scheme 1. Synthesis of indolylpyrrole derivatives by reaction between arylglyoxals, acetylacetone, indole and
aliphatic amines
Scheme 2. The possible reaction mechanism for synthesis of indolylpyrroles 5a-i.
Scheme 3. Synthesis of 3-acetyl-1-aryl-2-(1H-indol-3-yl)pentane-1,4-dione 7
Table 1. Synthesis of indolylpyrrole derivatives (5a- i) by reaction of arylglyoxals, acetylacetone, indole and
aliphatic amines
Table 2. Synthesis of 3-acetyl-1-aryl-2-(1H-indol-3-yl)pentane-1,4-diones 7a-g by reaction between
arylglyoxals, acetylacetone , indole and aliphatic amine.

Pyrrole ring is one of the most important chemical subunits
Indoles with a pyrrole ring at their C3 position possess biological activities
Multi-component reactions in water have attracted much attraction
Developing new efficient methods for synthesis of heterocycles are of interest

1
0
Tetrahedron