[bmim]OH promoted hydroalkynylation of nitrile and intramolecular hydroamination of the carbon-carbon multiple bond: An efficient and eco-compatible strategy for the synthesis of indolizinones

Article abstract of DOI:10.1039/c3ra41212a

An efficient and novel hydroalkynylation of 2-cyanopyridine with arylacetylene and a subsequent intramolecular hydroamination promoted by a basic ionic-liquid, [bmim]OH, under microwave activation in the absence of an organic solvent and an inorganic base, yielding biodynamic indolizinones has been developed. The protocol involves [bmim]OH mediated in situ generation and addition of a nucleophilic alkynide from the aryl substituted terminal on a carbon alkyne of a polar nitrile group of 2-cyanopyridine. This results in the formation of a 2-pyridylphenylethynyl methimine intermediate which, on subsquent intramolecular nucleophilic addition of a pyridyl nitrogen on the carbon-carbon triple bond of the imine intermediate, heterocyclized into indolizinone with high atom economy. The reaction proceeded smoothly and quantitatively at an ambient temperature. The task specific [bmim]OH was recovered and reused three times without any appreciable decrease in its activity and product yield. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ra41212a

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[bmim]OH promoted hydroalkynylation of nitrile and
intramolecular hydroamination of the carbon–carbon
multiple bond: an efficient and eco-compatible
strategy for the synthesis of indolizinones3
Cite this: RSC Advances, 2013, 3, 10173
Received 13th March 2013,
Accepted 26th April 2013
DOI: 10.1039/c3ra41212a
I. R. Siddiqui,* Afaf A. H. Abumhdi, Shayna Shamim, Shireen, Malik A. Waseem,
Rahila, Arjita Srivastava and Anjali Srivastava
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An efficient and novel hydroalkynylation of 2-cyanopyridine with
arylacetylene and a subsequent intramolecular hydroamination
promoted by a basic ionic-liquid, [bmim]OH, under microwave
activation in the absence of an organic solvent and an inorganic
base, yielding biodynamic indolizinones has been developed. The
protocol involves [bmim]OH mediated in situ generation and
addition of a nucleophilic alkynide from the aryl substituted
synthesis from N-(pent-2-en-4-ynyl)-lactams7 etc., but most of them
require expensive5,7,8 and toxic metal catalysts,9 molecular VOLs
(volatile organic liquids) as a reaction medium,10 and have a
tedious work-up process.11 Recently, a few relatively greener
protocols have also been employed for the synthesis of
indolizinones.12 But, there is still need for the development of a
straightforward, efficient, high yielding, atom economical, eco-
compatible synthetic protocol for indolizinones. Indolizinones,
therefore, appear to be attractive heterocyclic scaffolds for the
development of their synthetic protocols and for the exploration of
their chemical diversity in the drug discovery process and
screening the lead compounds.
Recently, ionic liquid (ILs), have attracted attention due to their
great potential as eco-friendly reaction media with a wide solvating
ability, negligible vapour-pressure and tunable properties. ILs are
reported to have displayed significant roles as catalysts, reaction
media and reagents and are easy to recover and reuse.13–15
Buoyed from the above facts and to circumvent the above-
mentioned drawbacks, as well as a part of our ongoing endeavour
for the construction of simple, efficient, versatile synthetic
methodologies for biodynamic heterocyclic scaffolds,16–22 we have
developed an eco-compatible, facile and atom economical
methodology using 2-cyanopyridine and phenylacetylene as
reactants, [bmim]OH as an alternative reaction medium and
promoter, and microwave activation as an alternative energy
source to furnish indolizinones in 72–98% yield (Scheme 1).
In order to achieve our objective efficiently and expeditiously,
we devised a task specific basic ionic liquid [bmim]OH promoted
tandem approach for the synthesis of indolizinones under
terminal on
a carbon alkyne of a polar nitrile group of
2-cyanopyridine. This results in the formation of a 2-pyridylphe-
nylethynyl methimine intermediate which, on subsquent intra-
molecular nucleophilic addition of a pyridyl nitrogen on the
carbon–carbon triple bond of the imine intermediate, hetero-
cyclized into indolizinone with high atom economy. The reaction
proceeded smoothly and quantitatively at an ambient tempera-
ture. The task specific [bmim]OH was recovered and reused three
times without any appreciable decrease in its activity and product
yield.
Introduction
The nitrile functionality (–CMN) is a key constituent of numerous
natural products and also serves as an important synthetic
intermediate for phamaceuticals,1 agricultural chemicals, dyes,
material science2 and as an intermediate in microbial metabo-
lism.3 Nitriles are important synthons in preparative organic
chemistry due their facile conversion into a variety of functional
groups.1–4 Nitrile compounds are viable precursors for the
preparation of a variety of nitrogen containing functional
compounds and the formation of a carbon–nitrogen bond in
the synthesis of a variety of biodynamic nitrogen heterocycles.4
Indolizinones have been prepared by using a variety of
protocols which includes the palladium catalysed domino reaction
of tertiary propargylic alcohols,5 copper-catalyzed cycloisomeriza-
tion of 2-pyridylsubstituted propargylic acetates,6 Au-catalyzed
Laboratory of Green Synthesis, Department of Chemistry, University of Allahabad,
Allahabad-211002, India. E-mail: dr.irsiddiqui@gmail.com
Scheme 1 TSBIL promoted synthesis of indolizinones under MW activation.
RSC Adv., 2013, 3, 10173–10176 | 10173
Electronic supplementary information (ESI) available. See DOI: 10.1039/c3ra41212a
3
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Table 2 Influence of different TSBILs in the synthesis of indolizinone under
microwave activationa
Entry
Catalyst
Mol% of catalyst
Time (min)
Yield (%)b
1
2
3
4
5
6
7
8
9
[bmim]Br
[bmim]OH
[bmim]PF4
[bmim]Cl
[bmim]OH
[bmim]OH
[bmim]OH
[bmim]OH
[bmim]OH
10
10
10
10
5
15
20
25
10
3
2
3
3
2
2
3
3
5
67
91
59
63
62
60
55
53
91
Scheme 2 Tentative mechanism for TSBIL promoted synthesis of indolizinones
under MW activation.
a
Reaction conditions: 2-cyanopyridine (2 mmol), phenyl acetylene (2
b
microwave activation. A tentative mechanism of the reaction is
given in Scheme 2.
mmol). Isolated yield.
To explore the feasibility of this strategy we attempted to
investigate the optimization of the reaction conditions in regard to
the catalyst, solvent, base, reaction time and yield of product, with
2-cyanopyridine and phenylacetylene as model substrates for the
representative compound 5a (Table 1).
The reaction was initiated by heating a mixture of 2-cyanopyr-
idine 1a (2 mmol), phenylethyne 2a (2 mmol) and K2CO3 (20
mol%) in C2H5OH under reflux for 5 h, where indolizinone 5a was
obtained, but only in 35% yield. The reaction was then carried out
using different bases like Et3N and NaOH and different solvents
like CH2Cl2 and DMF and the results are summarized in (Table 1).
Results show that in the case of solvent C2H5OH and base
NaOH, 62% yield (Table 1, entry 3) was obtained, but in case of
other solvents and other bases the yields of the product were only
35–45% (Table 1, entries 1, 2, 4–9). Thus, in terms of yield of
product, C2H5OH is the best solvent and NaOH is the best base.
Persuaded by the reports illustrating the use of TSBIL (task
specific basic ionic liquid) [bmim]OH in many organic transfor-
mations, we employed [bmim]OH as a promoter and as an
alternative reaction medium in the reaction between 2-cyanopyr-
idine and phenylacetylene, and, to our surprise, a smooth
conversion of starting material into indolizinone with an excellent
yield of 80% was observed when they were stirred for 1 h (Table 1,
entry 11). Encouraged with the result, the same reaction was
carried under microwave activation (Table 3). Reactants were
transformed into the product in almost the same yield but in
considerably less time (2–3 min).
The reaction was also carried by using various ILs like
[bmim]OH, [bmim]Br, [bmim]PF4 and [bmim]Cl, but the best
result in terms of yield of product was obtained with [bmim]OH.
Table 1 Optimization of reaction conditions for the synthesis of representative compound 5aa
Entry
Catalyst (5 mol%)
Base (20 mol%)
Solvent
Temp
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
—
K2CO3
NEt3
NaOH
K2CO3
NEt3
NaOH
K2CO3
NEt3
NaOH
NaOH
—
C2H5OH
C2H5OH
C2H5OH
CH2Cl2
CH2Cl2
CH2Cl2
DMF
DMF
DMF
H2O
[bmim]OH
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
r.t.
5
6
5
4
3
2
3
2
5
5
1
35
39
62
42
38
45
41
37
44
31
80
9
10
11
a
b
Reaction conditions: 2-cyanopyridine (2 mmol), phenylacetylene (2 mmol), [bmim]OH (10 mol%). Isolated yield.
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Table 3 TSBIL [bmim]OH promoted synthesis of indolizinone 5(a–j) under
microwave activationa
Table 3 (Continued)
Product
5(a–j)
Time Yield
(min) (%)b
Entry 1(a–c)
2(a–f)
9
2
82
10
3
86
Product
5(a–j)
Time Yield
(min) (%)b
Entry 1(a–c)
2(a–f)
1
2
85
a
Reaction conditions: 2-cyanopyridine (2 mmol), phenyl acetylene (2
b
mmol), [bmim]OH (10 mol%). Isolated yield.
2
3
4
3
82
The reaction was then carried out using 5 mol%, 10 mol%, 15
mol%, 20 mol% and 25 mol% of [bmim]OH. Using 5 mol%
[bmim]OH, gave a 62% yield of the product which is lower than
that obtained in case of 10 mol% (Table 2, entry 4, 1). It was
observed that the increase in mol% of [bmim]OH decreases the
yield to 60%, 59%, 55% and 53%, respectively (Table 2, entry 5, 6,
7, 8). It was also observed that best yield of the product was
obtained when the reaction mixture was exposed to microwave
activation for 2–3 min. Yield of the product did not increase by
extending the exposure time.
2
2
97
87
Thus, the optimum conditions in terms of yield of the product
are [bmim]OH in 10 mol% microwave irradiation for 2–3 min
(Table 2, entry 1). However with other solvents, base, mol% and
exposure time, the yield was appreciably low (Table 1). The present
optimized synthesis is accomplished by irradiation of the reaction
mixture of 2-cyanopyridine 1 (2 mmol), phenyl acetylene 2 (2
mmol), [bmim]OH (10 mol%) with microwave irradiation for 2–3
min. Isolation and purification of the product afforded indolizi-
nones 5 in 80–92% yield. The progress of reaction was monitored
by TLC. The [bmim]OH was recovered and reused three times
without any appreciable decrease in its activity and yield of the
product (Fig. 1).
5
3
98
6
7
2
3
80
86
Conclusion
In summary, we have developed an original, convenient, atom
economical, eco-compatible and task specific basic ionic liquid,
[bmim]OH, promoted tandem approach under microwave activa-
8
3
81
Fig. 1 Recycling of [bmim]OH.
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Acknowledgements
The authors acknowledge the Libiyan embassy for the research
grant. The authors were also thankful to the Central Drug
Research Institute (CDRI), Lucknow for providing spectral
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10176 | RSC Adv., 2013, 3, 10173–10176
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