Microwave-assisted catalyst-free synthesis of tetrasubstituted pyrroles using dialkyl acetylenedicarboxylates and monophenacylanilines

Article abstract of DOI:10.1080/00397911.2016.1176201

An efficient catalyst-free microwave-assisted synthesis of tetrasubstituted pyrroles using dialkyl acetylenedicarboxylates and substituted monophenacylanilines has been developed. Axial chirality has been noticed in some N-(α-naphthyl/2-isopropylphenyl)-2

Full text of DOI:10.1080/00397911.2016.1176201

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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Microwave - Assisted Catalyst- Free
Synthesis of Tetrasubstituted Pyrroles
Using Dialkyl Acetylenedicarboxylates and
Monophenacylanilines
Arumugam Mariappan, Kandasamy Rajaguru, Shanmugam
Muthusubramanian & Nattamai Bhuvanesh
To cite this article: Arumugam Mariappan, Kandasamy Rajaguru, Shanmugam
Muthusubramanian & Nattamai Bhuvanesh (2016): Microwave - Assisted Catalyst-
Free Synthesis of Tetrasubstituted Pyrroles Using Dialkyl Acetylenedicarboxylates and
Monophenacylanilines, Synthetic Communications, DOI: 10.1080/00397911.2016.1176201
To link to this article: http://dx.doi.org/10.1080/00397911.2016.1176201
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Date: 19 April 2016, At: 23:45

Microwave - Assisted Catalyst- Free Synthesis of Tetrasubstituted Pyrroles Using
Dialkyl Acetylenedicarboxylates and Monophenacylanilines
1
1
1
Arumugam Mariappan , Kandasamy Rajaguru , Shanmugam Muthusubramanian ,
2
Nattamai Bhuvanesh
1
Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University,
2
Madurai, India, X-ray Diffraction Laboratory, Department of Chemistry, Texas A & M
University, College Station, Texas, TX, USA
Corresponding author: Shanmugam Muthusubramanian, E-mail:
muthumanian@yahoo.com
Abstract
An efficient catalyst free microwave assisted synthesis of tetrasubtituted pyrroles using
dialkyl acetylenedicarboxylates and substituted monophenacylanilines has been
developed. Axial chirality has been noticed in some N-(α-naphthyl/2-isopropylphenyl)-
2
,3-dicarbethoxy-4-arylpyrroles, but not with N-aryl-2,3-dicarbethoxy-4-(α-
naphthyl)pyrrole.
KEYWORDS: Diethylacetylene dicarboxylate; Polysubtituted pyrrole; Microwave
synthesis; Axial chirality
INTRODUCTION
[
1]
Pyrrole nucleus can be found in many natural bioactive molecules, synthetic
[
2]
[3]
pharmaceuticals and functional materials with varied applications. Several
[
4]
[5]
polysubstituted pyrroles, in particular, are effective as anti-bacterial, anti-convulsant,
[
6]
[7]
[8]
[9]
anti-cancer, anti-oxidant, anti-tumour and anti-inflammatory agents. It must be
1

pointed out that pyrrole skelton has been found as a subunit in heme, chlorophyll, bile
pigments and vitamin B12 apart from alkaloids derived from marine sources. Some
popular pyrrole containing drugs are shown in Figure 1. Pyrrole derivatives have also
1
0
been widely used as organic conducting materials.
[
11]
[12]
The pyrrole unit can be generated from routes proposed by Knorr,
Paal−Knorr, and
[
13]
[14]
Hantzsch and the other strategies include the transition metal mediated cyclisation,
[
15]
[16]
[17]
reductive coupling, isocyanide based reactions, rearrangement reaction and
[
18]
cycloaddition methods.
The present investigation reports the synthesis of the
polysubstituted pyrroles, dialkyl 1,4-diaryl-1H-pyrrole-2,3-dicarboxylates. Though there
are many reports for the synthesis of the dialkyl 1,5-diaryl-1H-pyrrole-2,3-
[
19]
dicarboxylate, only a few reports describe the route for its regioisomer, dialkyl 1,4-
diaryl-1H-pyrrole-2,3-dicarboxylate. Abbasinejad et al first reported a two-step strategy
involving triphenylphosphine catalyzed cyclisation of α-aminoketones with dialkyl
[20]
acetylenedicarboxylates followed by chromium trioxide oxidation. Ardakani et al
reported triphenylphosphine promoted condensation reaction between dialkyl
[
21]
acetylenedicarboxylates and 1-aryl-2-(arylamino)-2-hydroxyethanones. A direct four-
component coupling reaction of aldehydes, amines, dialkyl acetylenedicarboxylates, and
[
22a]
nitromethane using iodine as a catalyst has been reported
and also an iron(III)
chloride catalysed three-component reaction of primary amines, dialkyl
[
22b]
acetylenedicarboxylates and β-nitrostyrene reported by Ghabraie et al.
Very recently,
Jeong et al reported one-pot four component, reaction of amines, aldehydes, dialkyl
2

acetylenedicarboxylates and nitroalkanes using silica supported ceric ammonium nitrate
[22c]
as a heterogeneous catalyst.
Liu et al reported a gold-catalyzed cascade
[
23]
hydroamination/cyclization reaction of α-amino ketones with alkynes. These protocols
involve (i) tedious task of removing the triphenylphosphine oxide or (ii)
prefunctionalisation of the monophenacylaniline part or (iii) more steps to reach the
desired product or (iv) long reaction time or (v) cascade hydroamination/cyclization
reaction where expensive gold has been used as the catalyst. To overcome these
shortcomings and exploiting the advantages of microwaves in modern synthetic organic
chemistry, the present scheme for pyrrole synthesis has been proposed in continuation of
[
24]
our work on the development of useful synthetic methodologies for the construction of
heterocycles. A microwave assisted catalyst free efficient synthesis of dialkyl 1,4-diaryl-
1
H-pyrrole-2,3-dicarboxylates from α-amino ketones with dialkyl
acetylenedicarboxylates has been achieved (Scheme 1).
RESULTS AND DISCUSSION
We started our investigation with 1a as the model substrate and treated that with DEAD
in THF without catalyst at room temperature. It must be admitted that a related reaction
has been reported involving acidic reagent with limited substrate scope after isolating the
[
25a]
intermediate.
Our strategy involves no acidic reagent, no isolation of the intermediate
and a wide substrate scope. Similar work yielding 2-trifluormethyl substituted pyrrole has
[
25b]
been reported very recently.
After 16 hrs, 3a was formed in 50% yield (Table 1, entry
1
) with 25% of starting material, the remaining being unrecognizable mass. Increasing
the reaction time had no impact on the yield of 3a. Carrying out the reaction in acetic acid
3

also did not enhance the yield as expected, but resulted in additional by-products as
evidenced by TLC. However, when the reaction was carried out in DMF under reflux
without any catalyst, the reaction got completed within 6 hrs (Table 1, entry 2) with 62%
yield of 3a. When we investigated the reaction by applying microwave with varying MW
power, temperature and the solvents (Table 1, entries 3-9), we found that 3a was obtained
o
in good yield with DMF in 110W at 110 C (Table 1, entry 9) in 10 minutes. Increasing
the reaction time beyond 10 minutes did not improve the yield, rather a slight decrease in
the yield has been observed as evidenced by TLC. The yield was relatively good with
solvents like ethanol, acetonitrile and water (Table 1, entries 13-15), but it was relatively
poor with the other solvents such as toluene, 1,4 dioxane and 1,2 DCE (Table 1, entries
1
0-12). The one pot reaction of all three compounds, as reported in the previous
[
19]
literature, resulted in diethyl 1,5-diphenyl-1H-pyrrole-2,3-dicarboxylate. Here the
reaction of aniline with the diethyl acetylenedicarboxylate was preferred over the
formation of monophenacylaniline. The initial reaction between aniline to phenacyl
bromide followed by the addition of DEAD could afford the desired product. When we
attempted the one pot synthesis through the addition of aniline to phenacyl bromide under
o
MW for 1 min at 110 C followed by the addition of DEAD, it resulted in lower yield of
the dialkyl 1,4-diaryl-1H-pyrrole-2,3-dicarboxylate. This may be due to the initial
formation of α,α’-amino ketones preventing the formation of the pyrrole. After
optimization we investigated the scope of the reaction and it worked well with variety of
α-aminoketones and different acetylene esters (Table 2). The structures of the products 3
has been unambiguously assigned by spectral and analytical data, and that of 3d has been
[
26]
confirmed by single crystal X-ray analysis as well [Figure. 2]. A closely related
4

[
23]
methodology employing gold catalyst has reported the synthesis of similar skeleton,
whereas the present work uses no catalyst generating a library of eighteen compounds.
It is pertinent to note that this cyclisation occurred successfully with both electron
withdrawing as well as electron donating groups in the aryl ring (Table 2). Presence of
electron withdrawing groups on the carbonyl attached phenyl ring and the electron
donating groups on the aniline ring of the monophenacylaniline promoted the formation
of product enhancing the yield of the desired product (Table 2, compounds 3d, 3e, 3i and
3
q). All the other monophenacylaniline derivatives differing from the aforementioned
combination of electron withdrawing and donating groups afforded moderate yield (Table
). Based on the observed results, a plausible mechanism is proposed (Scheme 2).
2
Initially the reaction of α-amino ketones with electron deficient alkynes afforded the
enamine intermediate A. Then the nucleophilic attack of the enamine to the carbonyl
group afforded intermediate B followed by the elimination of water provided the desired
product 3.
One out of the two sets of methylene hydrogens in 3j, 3l and 3p are found to be
diastereotopic indicating that chirality has arisen due to the restricted rotation around N-
(α-naphthyl/N-(2-isopropylphenyl) bond in these cases. In the case of 3i, the diasterotopic
1
13
behavior has been felt with the isopropyl methyls as well, both in the H and C NMR
spectra. It must be noted that when a simple methyl is present in the 2-position of the N-
2
2c
phenyl ring, no chirality has been noticed. It is also interesting to note that the presence
5

th
of α-naphthyl group in the 4 position of the pyrrole (3o) has not raised any chiral
characteristics.
CONCLUSION
In summary, we have developed a microwave assisted synthesis of dimethyl 1,4-
diphenyl-1H-pyrrole-2,3-dicarboxylates, the main advantage of this method being that it
is catalyst free with shorter reaction time resulting in good to excellent yield. Another
interesting feature is the realisation of axial chirality in N-(α-naphthyl/2-
isopropylphenyl)-2,3-dicarbethoxy-4-arylpyrroles, but not in N-aryl-2,3-dicarbethoxy-4-
(α-naphthyl)pyrrole.
EXPERIMENTAL SECTION
All solvents were purchased from commercial sources and used without further
purification. The melting points were measured in open capillary tubes and are
uncorrected. A CEM Discover microwave synthesizer (Model No: 908010) operating at
1
80/264 V and 50/60 Hz with microwave power maximum level of 300 W and
microwave frequency of 2455 MHz was employed for the microwave-assisted
1
13
experiments. Nuclear Magnetic Resonance ( H and C NMR) spectra were recorded on a
3
00 MHz spectrometer in CDCl using TMS as an internal standard. Chemical shifts are
3
reported in parts per million ( ), coupling constants (J values) are reported in Hertz (Hz)
and spin multiplicities are indicated by the following symbols: s (singlet), d (doublet), t
1
3
(
triplet), q (quatret), sept (septet), m (multiplet). C NMR spectra were routinely run
6

with broadband decoupling. Elemental analyses were performed on a Perkin Elmer
400Series II Elemental CHNS analyzer.
2
General Procedure for the Synthesis of Dimethyl 1,4-Diphenyl-1H-Pyrrole-2,3-
Dicarboxylate 3
A mixture of substituted monophenacylaniline 1 (1 mmol), dialkyl
acetylenedicarboxylate 2 (1.1 mmol) in DMF (1 mL) was sealed and subjected to
microwave irradiation programmed at 110 °C and 110 W for 10 minutes. The completion
of the reaction was monitored by TLC. The reaction mixture was extracted with ethyl
acetate. The organic layer was washed with water and brine, dried over anhydrous
sodium sulfate and concentrated in vacuum. Crude product was purified by column
chromatography using petroleum ether − ethyl acetate (5: 95) as the eluent to get 3.
Selected Spectral Data For Diethyl 4-(4-Chlorophenyl)-1-(P-Tolyl)-1H-Pyrrole-2,3-
Dicarboxylate (3d) are Given Below
o
1
Yellow solid; mp 97 – 100 C; H NMR (300 MHz, CDCl ) δ 7.40 – 7.31 (m, 4H), 7.27 –
3
7
3
1
1
3
4
.21 (m, 4H), 6.94 (s, 1H), 4.31 (q, J = 7.1 Hz, 2H), 4.18 (q, J = 7.1 Hz, 2H), 2.41 (s,
1
3
H), 1.29 (t, J = 7.1 Hz, 3H), 1.18 (t, J = 7.1 Hz, 3H). C NMR (75 MHz, CDCl ) δ
3
65.9, 159.9, 138.5, 136.8, 132.9, 131.8, 129.4, 129.1, 128.6, 125.8, 125.5, 123.9, 123.5,
21.2, 61.3, 60.9, 21.1, 14.0, 13.9. Anal. Calcd for C H ClNO : C, 67.07; H, 5.38; N,
23
22
4
+
.40 %. Found: C, 67.09; H, 5.33; N, 3.43 %. ESI-MS m/z calcd [M+H] 412.12, found
12.11.
7

ACKNOWLEDGEMENTS
We thank DST, New Delhi, for assistance under the IRHPA program for the NMR
facility and financial support from UGC MRP (major research project) F. No. 41-
2
65/2012(SR), New Delhi. A.M. gratefully acknowledges UGC for the award of a Junior
Research Fellowship.
SUPPORTING INFORMATION
Supplemental data for this article can be accessed on the publisher’s website.
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[
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26] CCDC number for 3d: 14336.
2
2
(
[
1
2

a
Table 1. Optimization of the reaction conditions
c
Entry Solvent
Temp
MW
(Watt)
-
Time
Yield of
o
(
-
C)
(mins)
960
360
10
3(%)
50
62
56
55
53
68
62
52
80
48
45
37
60
58
65
b
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
THF
d
DMF
140
100
100
100
110
120
120
110
110
-
THF
100
120
110
120
100
110
110
110
110
110
110
110
110
EtOH
MeCN
DMF
10
10
10
Water
Toluene
DMF
10
10
10
0
1
2
3
4
5
Toluene
10
1,4 Dioxane 110
10
1,2 DCE
MeCN
EtOH
110
110
110
110
10
10
10
Water
10
1
3

a
b
Reaction conditions: 1a (1mmol), 2 (1.1 mmol), solvent (1 ml) for 10 min. Reaction at
c
d
room temperature. Isolated yield. Reaction at reflux condition.
1
4

Table 2. Synthesised compounds (3a-3u)
1
5

Scheme 1. Synthesis of 1,2,3,4-tetrasubstituted pyrroles
1
6

Scheme 2. A plausible mechanism for the formation of 3
1
7

Figure 1. Examples of pyrrole derived drugs
1
8

Figure 2. Crystal structure of 3d
1
9