Efficient, Three-Component Synthesis of Pyrrole Derivatives Catalyzed by Iodobenzene and Oxone

Article abstract of DOI:10.1080/00397911.2015.1066392

A simple and highly efficient three-component method using easily available amines, nitrostyrene, and diketones in one pot has been developed for synthesis of pyrroles in the presence of catalytic amounts of iodobenzene and Oxone as oxidant. The protocol has been used to afford wide range of pyrroles in moderate to good yields.

Full text of DOI:10.1080/00397911.2015.1066392

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An Efficient, Three-Component Synthesis of Pyrrole
Derivatives Catalyzed by Iodobenzene and Oxone
Prashant B. Jagadhanea, Nikhil C. Jadhava, Omkar P. Herlekara & Vikas N. Telvekara
a Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology,
Matunga, Mumbai, India
Accepted author version posted online: 15 Jul 2015.
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To cite this article: Prashant B. Jagadhane, Nikhil C. Jadhav, Omkar P. Herlekar & Vikas N. Telvekar (2015): An Efficient,
Three-Component Synthesis of Pyrrole Derivatives Catalyzed by Iodobenzene and Oxone, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, DOI: 10.1080/00397911.2015.1066392
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AN EFFICIENT, THREE-COMPONENT SYNTHESIS OF PYRROLE
DERIVATIVES CATALYZED BY IODOBENZENE AND OXONE
Prashant B. Jagadhane1, Nikhil C. Jadhav1, Omkar P. Herlekar1, Vikas N. Telvekar1
1Department of Pharmaceutical Sciences and Technology, Institute of Chemical
Technology, Matunga, Mumbai, India
Address correspondence to Vikas N. Telvekar, Department of Pharmaceutical Sciences
and Technology, Institute of Chemical Technology, Matunga, Mumbai, India. E-mail:
vikastelvekar@rediffmail.com
Abstract
A simple and highly efficient three-component method using easily available amines,
nitrostyrene and diketones in one pot has been developed for synthesis of pyrroles in
presence of catalytic amount of iodobenzene and Oxone® as oxidant. The protocol has
been used to afford wide range of pyrroles in moderate to good yields.
KEYWORDS: Three-component; Pyrrole; Iodobenzene; Oxone®
INTRODUCTION
Pyrrole ring is an important structure, as it is found in pharmaceuticals, natural products,
polymer sciences, and metal coordinating ligands. In pharmaceutical chemistry,
compounds with pyrrole ring system exhibited significant biological activities like
antitumor, anti-inflammatory, antibiotic, and hypolipidemic.[1-4] Thus, synthesis of
pyrroles is of great importance in organic synthesis. Classical methods available for
1

pyrrole synthesis are Knorr, Pall-Knorr and Hantzsch approach. New methodologies for
pyrrole synthesis include intramolecular cyclization,[5-7] transition-metal catalyzation,[8-11]
and multi-component reactions.[12-15]
All these methods are suffering from drawbacks of tedious workups, use of toxic or
expensive transition metals, and unavailability of the starting materials. Therefore, simple
method to synthesize pyrrole derivatives under mild reaction conditions is still desirable.
Previously, we reported three-component synthesis of pyrroles using
(diacetoxyiodo)benzene.[16] Our lab is working on development of novel methodologies
using iodine reagents. In recent years, many methodologies have been developed to avoid
the use of iodoarene in an equimolar amount, by use of terminal oxidants such as m-
chloroperoxybenzoic acid or Oxone®.[17-20]
Herein, we report three-component synthesis of pyrrole derivatives by using catalytic
amount of iodobenzene and Oxone® (2KHSO5.KHSO4.K2SO4) as an environmentally
safe and cheap terminal oxidant. It has been reported in the literature that when
iodobenzene and Oxone® reacted an active iodine species called
hydroxy(phenyl)iodonium ion is generated in situ.[21]
RESULTS AND DISCUSSION
Aniline, acetylacetone and nitrostyrene were chosen as the model substrate for
optimization of reaction conditions and heated in acetonitrile in presence of 1 equivalent
iodobenzene and 1.5 equivalents Oxone®. The desired product 1-(2-methyl-1,4-diphenyl-
2

1H-pyrrol-3-yl)ethanone was obtained with moderate yield at refluxed condition (scheme
1). No product was observed when reaction was carried out at room temperature.
To study the solvent effect, the above reaction was carried out in various solvents such as
acetonitrile/water (1:1, v/v), THF, methanol, DMF and ethanol instead of acetonitrile
(Table 1). It was found that ethanol is the best suitable solvent for this reaction and gives
higher yield as compared to other solvents. Addition of 4 Å molecular sieves in small
amount improved yield of a product. From number of experiments we obtained
comparative yield with 0.2 equivalent iodobenzene and 1 equivalent Oxone® in presence
of 4 Å molecular sieves. With these optimized reaction conditions, different amines,
nitrostyrenes and 1,3-dicarbonyl compounds were used to evaluate the scope of the
reaction and results are presented in Table 2.
The protocol was applicable to various ranges of amines and it was noteworthy that
benzylamines and phenylethylamines reacted more smoothly than anilines to form
product in higher yields (Table 2, entries 1-9). Under this reaction conditions methoxy
groups are stable (Table 2, entries 10-12). Substitutions on phenyl ring of nitrostyrenes
had no effect on reactivity and both electron-donating and electron-withdrawing groups
afforded the good yields. Strong electron-withdrawing group like nitro substitution on
aniline showed no reaction (Table 2, entry 16).
In summary, we have developed an efficient, catalytic, three-component method for
synthesis of pyrrole from easily available chemical moieties like amines, nitrostyrenes
3

and 1,3-dicarbonyl compounds using iodobenzene and Oxone®. The protocol is versatile
and moderate to good yields were obtained from a broad range of amines, nitrostyrenes,
and 1,3-dicarbonyl compounds.
EXPERIMENTAL
General Procedure For Synthesis Of 1-(2-Methyl-1,4-Diphenyl-1H-Pyrrol-3-
Yl)Ethanone (Table 2, Entry 1)
To a previously stirred mixture of iodobenzene (0.041 g, 0.2 mmol) and Oxone® (0.307
g, 1.0 mmol) in ethanol (10 mL) for 15 min at room temperature, aniline (0.093 g, 1
mmol), nitrostyrene (0.164 g, 1.1 mmol), acetylacetone (0.100 g, 1 mmol) and 4 Å
molecular sieves (0.100 g) were added. The resultant reaction mixture was stirred at
reflux temperature. After the completion of the reaction (monitored by TLC), the reaction
mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 X 30 mL).
The combined organic layer was washed with brine and dried over anhydrous sodium
sulphate. The solvent was evaporated and crude residue was purified by column
chromatography to obtain the pure product.
White solid; Mp 104-106 oC (Lit.[14] 105-107 oC); IR (neat): 3059, 3029, 1651, 1503,
1402, 1223 cm-1; 1H NMR (300 MHz, CDCl3): δ 2.10 (s, 3H), 2.42 (s, 3H), 6.67 (s, 1H),
7.31-7.43 (m, 7H), 7.45-7.50 (m, 3H).
FUNDING
4

PBJ thanks Rajiv Gandhi National Fellowship (RGNF) and VNT thanks the Science and
Engineering Research Board (SERB), New Delhi, India, for providing financial support
SUPPORTING INFORMATION
Experimental method, 1H NMR, 13C NMR, IR and MP/BP for this article can be accessed
on the publisher’s website.
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6

Table 1. Optimization of reaction conditionsa
Entry
1
Iodobenezene Oxone® Solvent
Temp/Time
(ºC/h)
% Yieldb
(equiv.)
1
(equiv.)
1.5
Acetonitrile
RT/8
No
reaction
45
2
3
1
1
1.5
1.5
Acetonitrile
acetonitrile/water
(1:1, v/v)
THF
Reflux/5
Reflux/5
36
4
1
1.5
1.5
1.5
1.5
1.5
1.5
1
Reflux/5
Reflux/5
100/5
43
50
38
70
71
78
77
78
77
78
78
55
5
1
Methanol
DMF
6
1
7
1
Ethanol
Ethanol
Reflux/5
Reflux/2
Reflux/2
Reflux/2
Reflux/2
Reflux/2
Reflux/2
Reflux/2
Reflux/5
8
9c
1
1
Ethanol
10c
11c
12c
13c
14c
15c
1
Ethanol
0.8
0.6
0.4
0.2
0.1
1
Ethanol
1
Ethanol
1
Ethanol
1
Ethanol
1
Ethanol
aReaction conditions: aniline (1 mmol), nitrostyrene (1.1 mmol) and acetylacetone (1
mmol).
bIsolated yields. c 4 Å molecular sieves (0.100 g) added
7

a ,b
Table 2. Synthesis of pyrroles using Oxone® and Iodobenzene
Entry
1
R1
R2
R3
% Yieldc
78
Ph
Ph
CH3
CH3
OEt
OEt
CH3
CH3
OEt
CH3
OEt
CH3
CH3
OEt
CH3
OEt
CH3
CH3
2
Ph
p-ClC6H4
Ph
74
3
Ph
83
4
Ph
p-MeC6H4
Ph
78
5
PhCH2
86
6
PhCH2
p-FC6H4
Ph
80
7
PhCH2
82
8
PhCH2CH2
PhCH2CH2
p-OMeC6H4
p-BrC6H4
p-BrC6H4
p-ClC6H4
p-ClC6H4
Cyclohexyl
p-NO2C6H4
Ph
89
9
Ph
85
10
11
12
13
14
15
16
Ph
80
p-OMeC6H4
p-OMeC6H4
p-ClC6H4
Ph
79
75
82
80
p-ClC6H4
Ph
82
NR
aReaction conditions: amines (1 mmol), nitrostyrenes (1.1 mmol) and 1,3-dicarbonyl
compounds (1 mmol) using iodobenzene (0.2 mmol), Oxone® (1 mmol) and 4 Å
molecular sieves at reflux temperature in ethanol. bAll previously reported products were
identified by comparison of their NMR spectra and melting points with literature data.
cIsolated yields of analytically pure products. NR: No reaction
8

Scheme 1: Synthesis of pyrrole using iodobenzene and Oxone®
9