Tetrahedron Letters
Multicomponent reactions in PEG-400: ruthenium-catalyzed
synthesis of substituted pyrroles
a,
⇑
a
a
a
b
Srivari Chandrasekhar , Vidyavathi Patro , Lahu N. Chavan , Rambabu Chegondi , René Grée
a
Division of Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
Université de Rennes 1, Institut des Sciences Chimiques de Rennes, CNRS UMR 6226, Avenue du Général Leclerc, 35042 Rennes Cedex, France
b
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and eco-friendly method for the synthesis of substituted pyrroles has been developed via
ruthenium-catalyzed multicomponent reaction of ketone, amine, and ethylene glycol in PEG-400 as
solvent medium without using any external ligand. The catalytic system and solvent can be recycled with
the same, as well as different, ketones with minimum loss of Ru-catalyst activity.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 20 June 2014
Revised 25 August 2014
Accepted 27 August 2014
Available online xxxx
Keywords:
Pyrrole
Multicomponent reaction
Ruthenium
Eco-friendly
Polyethylene glycol (PEG-400)
1
2
Multicomponent reactions (MCRs), eco-friendly solvents, and
The results pertaining to Ru-catalyzed three-component pyrrole
synthesis with a recyclable medium (Ru and PEG-400) are reported
herein (Scheme 1). Furthermore, a significant advantage of the
described method is that the expensive ligand (xantphos) is
3
catalysis have been central themes in green chemistry. Incorpora-
tion of these principles into the formation of new C–C and C–X
bonds paves the way toward the preparation of new chemicals
and products in agrochemicals, pharmaceuticals, and materials in
an economical fashion. In particular, the use of recyclable and
1
4
avoided since the PEG-400 acts as external ligand.
In the first instance, cyclopentanone 1a, cyclohexylamine 2a,
and ethylene glycol 3 were chosen as partners in the [2+2+1] con-
densation process (Table 1, entry 1). The reaction in PEG-400 in
4
reusable solvents is gaining prominence in organic reactions. In
this direction, we have demonstrated in our early studies that
PEG-400 is a preferred solvent medium wherein the expensive
metals and their complex could be recovered and reused effec-
tively without loss of activity.5
2 2
the presence of 1 mol % [RuCl (p-cymene)] and 20 mol % t-BuOK
catalytic system was successful and 1,2,3-trisubstituted pyrrole
5k,15
4a was isolated in 75% yield, after a routine work-up process.
Since the first synthesis of ‘pyrrole’ ring by Knorr way back in
With this observation on hand, the reaction generality was studied
by performing experiments with various substrates. Keeping
cyclopentanone 1a and ethylene glycol 3 as the common partners,
4-methoxybenzylamine 2b (Table 1, entry 2) and n-butyl amine
2c (Table 1, entry 3) as variable amine counterparts, pyrroles 4b,
4c were obtained in decent yields. To understand the patterns for
aryl ketones, phenylethylketone 1b and ethylene glycol 3 as
1
884, the preparation of pyrroles has come a long way over the
6
7
past century. Several approaches viz., [3+2] cycloadditions,
8
9
10
[
4+1] approach, [2+2+1] approach, and intramolecular versions
have been developed for the synthesis of pyrroles. These
1
1
approaches are compiled in excellent reviews by Ferreira and
1
2
Menendez. Recently, a novel three-component method for the
pyrrole synthesis has been reported by Beller’s group using
ruthenium catalysis, assisted by xantphos as ligand, in a [2+2+1]
strategy for the pyrrole formation.13 This work combined with
[RuCl
2
(p-cymene)]
2
R2
O
(
1 mol%)
5
R3 NH
HO
+
our experience in using PEG-400 as a solvent medium, prompted
R
2
+
2
OH
R1
t-BuOK (20 mol%)
R1
us to look at the recyclability of expensive Ru-catalyst in such a
pyrrole synthesis.
N
o
PEG-400, 130 C
1a-1e
2a-2j
3
3
R
1
6 h-24 h
1
2
3
R = aryl, alkyl R = alkyl, aryl
R = H, alkyl
4
a-4r
⇑
Scheme 1. Synthesis of substituted pyrroles in PEG-400.
040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
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