A one-pot sequential five-component domino reaction for the expedient synthesis of polysubstituted pyrroles

Article abstract of DOI:10.1039/c5nj03444b

A series of novel pyrrole derivatives has been synthesized from readily available acetophenone, N,N-dimethylformamide dimethyl acetal, aniline, arylglyoxal and malononitrile in methanol under reflux conditions. This one-pot reaction constitutes a new and

Full text of DOI:10.1039/c5nj03444b

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A one pot sequential five component domino reaction for expedient
synthesis of polysubstituted pyrroles
Sethurajan Ambethkara, Vediappen Padminia,*Nattamai Bhuvaneshb
a Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University,
Madurai 625021, Tamil Nadu, India
b X-ray Diffraction Laboratory, Department of Chemistry, Texas A&M University, College
Station, TX 77842, USA
*Correspondence author e-mail: padmini.chem@mku.org &
padimini_tamilenthi@yahoo.co.in
Keywords: Pyrrole, One-pot reaction, catalyst free synthesis.
Abstract
A series of novel pyrrole derivatives has been synthesized from readily available
acetophenone, N,N-dimethylformamaide dimethyl acetal, aniline, arylglyoxal and
malanonitrile in methanol under reflux condition.This one pot reaction constitutes a new and
rapid construction of a library of pyrroles. The synthesized compounds are characterized by
spectral techniques and single crystal X-ray study.
Introduction
Pyrrole represents an important skeletal structure1in wide variety of biologically active
natural products and their analogues are of great importance in medicinal chemistry (Fig 1).2
They have also been extensively used in synthetic pharmaceuticals,3 catalyst, conducting
polymers and dyes.4 Pyrrole and its derivatives have received much attention because of their
significant biological activities such as antifungal,5 antioxidant,6 antituberculosis,7 analgesic,8
anti-inflammatory,9 antidiabetic10and anticancer.11Additionally pyrrole is an important core
moiety in many biomolecules such as heme, chlorophyll, bile pigments, vitamin B12 and
alkaloids.12 There are only limited reports available regarding the C4-unsubstituted pyrroles.
In2010 Maiti13et al. reported FeCl3-catalyzed four-component coupling reaction for the

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synthesis of tetrasubstituted pyrroles, and later in 2012 Reddy14et al. reported a direct and
regioselective synthesis of tetrasubstituted pyrroles.
Figure 1. Representative examples of biologically active pyrrole derivatives.
A numerous alternative synthetic methodologies have been developed for the construction of
pyrrole ring and more frequently used protocols are Hantzsch, 15 Knorr16 and Paal-Knorr. 17
However, these classical methods have significant drawbacks such as multistep synthetic
operation, inaccessible starting materials, longer reaction times, lower yields, harsh reaction
conditions and lacks of regiospecificity. To overcome these limitations, some straightforward
and efficient strategies involving multicomponent reaction18 and transition metal - mediated
cyclization reaction19 have been developed.
Only few reports are available on polysubstituted pyrrole cyanoacetamides, Feng20et al.
reported the one pot four component reactions towards the synthesis of polysubstituted
pyrrole cyanoacetamide derivatives. Recently, Pramanik21et al. developed four component
domino protocols for pyrrole cyanoacetamide system via enaminone. Enaminones are readily
accessible versatile synthons having the ambient nucleophilicity of enamine and

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electrophilicity of enone. β-Enaminones have been exploited as building blocks for the
synthesis of many organic compounds.22 Based on the previous literature, we planned to
explore the use of N,N-dimethylformamaide dimethylacetal for the construction of
polysubstituted pyrrole cyanoacetamides through insitu generation of enaminone. It is
pertinent to note that there is no report available on the synthesis of 2-(4-benzoyl-1, 2-
diphenyl-1H-pyrrol-3-yl)-2-cyanoacetamide in one pot five component route.
Results and discussion
The polysubstituted pyrroles have been synthesized in the present work via a coupling
reaction involving acetophenone 1, N,N-dimethylformamaide dimethylacetal 2, substituted
amine 3, arylglyoxal 4 and malanonitrile 5 in 5 mL methanol under reflux condition for 1.5 h,
leading to a library of novel pyrrole cyanoacetamides 6aa-au in good yield 52- 83 %
(Scheme 1).
Scheme 1 Synthesis of 2-(4-benzoyl-1, 2-diphenyl-1H-pyrrol-3-yl)-2-cyanoacetamide.
To optimized the reaction condition, the formation of synthesis of the 2-(4-benzoyl-2-
phenyl-1-(p-tolyl)-1H-pyrrol-3-yl)-2-cyanoacetamides 6ag, has been taken as model
reaction. The significant role of solvents and temperature were recorded and the results are
listed in (Table 1). We first investigated the effect of solvent and the reaction was tested in
water under reflux condition. There is no product formation even after 12 h (Table 1, entry
1). Further optimization with different solvents such as THF, CH3CN, DMF and DCE under

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reflux conditions afforded the products in 51, 57, 62 and 45% yields respectively (Table 1,
entry 2- 5).Next we examined the reaction under different temperatures in the absence of
solvents, affording the product 6ag in 52-59% yield (Table 1, entry 6-7). Interestingly when
this reaction was carried out in5 mL of methanol in the absence of catalyst under reflux
condition for 1.5 h afforded maximum yield 83 % of the product (Table 1, entry 9). This
optimization results revealed that solvent and temperature play role on the reaction
efficiency.
Table1. Different Conditions for the Synthesis of substituted pyrroles 6aga
Entry
Solvent
Temp(°C)
Reflux
Time
Yield of 6 agb(%)
1
2
3
4
5
6
7
8
9
Water
THF
12 h
3 h
3 h
3 h
6 h
3h
3 h
1.5 h
1.5 h
---c
51
57
62
45
52
59
75
83
Reflux
Acetonitrile
DMF
DCE
Reflux
Reflux
Reflux
60
100
Reflux
Reflux
---d
---d
Ethanol
Methanol
a
Reaction conditions: acetophenone (1.0mmol), p-toluidine (1.0mmol), phenylglyoxal
b
monohydrate (1.0mmol) and malanonitrile (1.0mmol) in 5 mL of solvent. Isolated yield.
c
Product is not formed. d Solvent free reaction.

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Table 2: Synthesis of substituted pyrroles 6aa-aua
aIsolated yield.

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Using the optimized conditions, we employed differently substituted acetophenones, aryl (or)
alkyl amine and arylglyoxals (Table 2). The electron withdrawing and electron donating
substituents showed equal productivity without any significant effect on the yield of the
product, though the heteroaryl substituted pyrrole is obtained in poor yield (Table 2, entry
6au).
Figure. 2 ORTEP diagram of 6al.
The structures of all the new synthesized compounds were confirmed by spectral techniques
including NMR and ESI-MS. The structure of 6al was confirmed by X-ray crystallography as
well (figure 2). A plausible mechanism for the formation of product 6is shown in scheme 2.
The first intermediate 1a is formed by the formylation between acetophenone 1 and N,N-
dimethylformamaide dimethylacetal 2, which undergoes Michael addition with amine 3
followed by elimination of dimethylamine to form intermediate 7.21 Intermediate 8 is formed
by Knoevenagel condensation reaction between arylglyoxal monohydrate 4 and malanonitrile
5. Subsequently the Michael addition of enaminone intermediate 7 to intermediate 8 produces

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iminium ion intermediate 9, which then undergoes imine-enamine tautomerization followed
intramolecular cyclization leading to stable furano-pyrrole intermediate 12. Finally, the
polysubstituted pyrrole 6 is formed via ring opening of 12.
Scheme 2: Plausible mechanism for the formation of 2-(4-benzoyl-1, 2-diphenyl-1H-pyrrol-
3-yl)-2-cyanoacetamide.

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Conclusion:
In conclusion, we have successfully developed a one pot sequential five component reaction
for the synthesis of polysubstituted pyrroles under catalyst free conditions. The formation of a
C-C and a C-N bond in a single synthetic operation has been achieved. The synthesized
compounds have been characterised by NMR, MASS and single crystal X-ray studies. The
significant advantages of this protocol include easily accessible starting materials, short
reaction time, simple workup, no column chromatographic purification and good yields.
Experimental section:
1
The melting points were measured in open capillary tubes and are uncorrected. The H and
13C NMR spectra were recorded on a Bruker (Avance) 300 MHz NMR instrument using
TMS as internal standard either CDCl3 or DMSO-d6 as solvent. Chemical shift values are
given in parts per million (δ-scale) and the coupling constants are given in hertz (Hz). Silica
gel-G plates (Merck) were used for thin layer chromatography (TLC) analysis with a mixture
of petroleum ether (60-80 °C) and ethyl acetate as eluent. The single crystal X-ray data were
collected on Bruker GADDS X-ray (three-circle) diffractometer with Mo Kα(k= 1.5418 A˚)
radiation. Elemental analyses were performed on a vario EL III CHNS elemental analyzer.
Mass spectra were recorded in LCQ Fleet mass spectrometer, Thermo Fisher Instruments
Limited, US. Electrospray ionization mass spectrometry (ESI-MS) analysis was performed in
the positive ion and negative ion mode on a liquid chromatography ion trap.
General procedure for the synthesis of 2-(4-benzoyl-1, 2-diphenyl-1H-pyrrol-3-yl)-2-
cyanoacetamide:
A 25 mL round bottom flask equipped with a magnetic stirrer was charged with
acetophenone 1 (1.0 mmol) and DMF-DMA 2 (1.0 mmol). The reaction mixture was heated

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on an oil bath at 100 °C for 1 h and after one hour the colour of the reaction mixture was
changed colourless to reddish-brown. The other reactants amine 3 (1 mmol), arylglyoxal 4 (1
mmol) and malanonitrile 5 (1.0 mmol) in methanol 5mL were added to the reaction system
and the reaction mixture was stirred at 60-70 °C for 30 min. The completion of the reaction
was monitored by TLC. After completion of the reaction, the mixture was cooled to room
temperature and the solid product was filtered, washed with a small portion of cold ethanol to
obtain pure product 6.
Acknowledgements
S.A. is gratefully acknowledged for the Research Fellowship from UGC-RGNF. We thank
the DST, New Delhi for assistance under the IRHPA program for the NMR facility.
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Table of contents:
A new protocol towards the synthesis of polysubstituted pyrroles via enaminone from one pot
five component reactions under catalyst free conditions.