PEG-400 mediated sp3C[sbnd]H functionalization of aza-arenes: an enroute to the synthesis of 2-(2-(6-methylpyridin/quinolin-2-yl)-1-phenylethyl)malononitriles

Article abstract of DOI:10.1016/j.tetlet.2016.08.083

Polyethylene glycol (PEG-400) has been discovered to be an effective eco-friendly solvent cum activator for the one-pot coupling of 2,6-dimethyl-pyridine or 2-methylquinoline, malononitrile and aldehydes to produce aza-arene derivatives through a sp³

Full text of DOI:10.1016/j.tetlet.2016.08.083

Accepted Manuscript
PEG-400 mediated sp3 C-H functionalization of aza-arenes: an enroute to the
synthesis of 2-(2-(6-methylpyridin/quinolin-2-yl)-1-phenylethyl)malononi-
triles
Raghu Mallepalli, Dinesh Kumar Reddy Vennam, Ramu Sridhar Perali
PII:
S0040-4039(16)31120-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.08.083
TETL 48054
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
12 June 2016
25 August 2016
29 August 2016
Please cite this article as: Mallepalli, R., Vennam, D.K.R., Perali, R.S., PEG-400 mediated sp3 C-H functionalization
of aza-arenes: an enroute to the synthesis of 2-(2-(6-methylpyridin/quinolin-2-yl)-1-phenylethyl)malononitriles,
Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.08.083
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PEG-400 mediated sp3 C-H functionalization
of aza-arenes: an enroute to the synthesis of
2-(2-(6-methylpyridin/quinolin-2-yl)-1-
phenylethyl)malononitriles
Leave this area blank for abstract info.
Raghu Mallepalli,[a][b] Dinesh Kumar Reddy Vennam[a][b] and Ramu Sridhar Perali *[a]

1
Tetrahedron Letters
journal homepage: www.els evier.com
PEG-400 mediated sp3 C-H functionalization of aza-arenes: an enroute to the
synthesis of 2-(2-(6-methylpyridin/quinolin-2-yl)-1-phenylethyl)malononitriles
Raghu Mallepalli,[a][b] Dinesh Kumar Reddy Vennam [a][b] and Ramu Sridhar Perali *[a]
aSchool of Chemistry, University of Hyderabad, Hyderabad-500046, India
bBoth the authors contributed equally
ARTICLE INFO
ABSTRACT
Article history:
Received
Polyethyleneglycol (PEG-400) has been discovered to be an effective eco-friendly solvent cum
activator for the one-pot coupling of 2,6-dimethyl-pyridine or 2-methylquinoline, malononitrile
and aldehydes to produce aza-arene derivatives through a sp3 bond functionalization. The
reaction was performed under mild conditions and the generality of the one-pot reaction was
investigated.
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
PEG-400
aza-arenes
C-H functionalization
one-pot reaction
green chemistry
1. Introduction
Lewis acid catalysis. Recently, the addition of 2-alkylaza-arenes
to activated C=C has been achieved by Lewis acid catalysis.10
Green chemistry relates to the design of a process that
minimizes the use and generation of hazardous substances. Green
catalysis is one of the key areas of green chemistry. In the past
decade, the use of alternative solvents such as ionic liquids,
polyethylene glycol and super critical fluids has gained
importance as green reaction media in view of environmental
perception.1 In this context, PEG has become an alternative
reaction media to perform organic synthesis due to its inherent
advantages over toxic solvents. Furthermore, PEG has emerged
as a powerful phase transfer catalyst and performs many useful
organic transformations under mild reaction conditions. In
addition, PEG is inexpensive, easy to handle, thermally stable,
non-toxic and recyclable. In this perspective, PEG as a solvent
has been played a key role in the practice of green chemistry.2
However, to the best of our knowledge, a one-pot Knoevenagel
condensation of active methylene compound and an aldehyde
followed by the addition of sp3 C-H bond in 2-alkylaza-arenes to
give 2-substituted pyridine and quinolone derivatives is not yet
reported. In continuation of our work on PEG-400 mediated
transformations,11 herein we report an efficient synthesis of 2-(2-
(6-methylpyridin-2-yl)-1-phenylethyl)malononitrile derivatives,
via a one-pot Knoevenagel condensation followed by sp3 C-H
bond addition, using polyethylene glycol as a green solvent
through the condensation of 2,6-dimethylpyridine or 2-
methylquinoline, malononitrile and aldehydes under catalyst-free
conditions.
2. Results and discussion
On the other hand, substituted pyridines or quinoline
derivatives represent
PEG was shown to be a green solvent system for the
condensation of aldehydes with active methylene compounds.
Keeping the mild acidic characteristics of PEG and previous
reports on the sp3 C-H functionalization of 2-methyl aza-arenes
by Lewis acid catalysis, we envisaged that generation of an α,β-
unsaturated system insitu in presence of 2-methyl aza-arenes
might lead to the formation of 2-substituted aza-arene
derivatives. Thus, 2,6-dimethylpyridine 1 was treated with
benzaldehyde 2 and malononitrile 3 in PEG-400 as a solvent
system at room temperature. After stirring the reaction for 10 h
followed by general workup, the product 2-substituted aza-arene
a significant class of nitrogen-fused
heterocycles, which are ubiquitous in many natural products and
biologically active compounds.3 These compounds play an
important role in drug discovery and development. Many
synthetic and naturally occurring 2-substituted pyridines and
quinolines have found wide applications in treating
protozoal/retroviral co-infections,4 antileishmanial agents5 etc.
One of the intellectual protocol for the synthesis of 2-substituted
aza-arenes is through the sp3 C-H functionalization of 2-alkyl
pyridines and quinolones. This reaction is feasible particularly
due to the formation of enamine by increasing the acidity of the
derivatve,
2-(2-(6-methylpyridin-2-yl)-1-phenylethyl)
6
benzylic proton using suitable metal catalyst or a Lewis acid.
Activated sp3 C-H of 2-methyl pyridine and quinolones have
been reacted successfully with C=O,7 C=N8 and N=N9 using
malononitrile 4 was isolated in 62% yield (Scheme 1).
Interestingly, when the reaction was conducted at 85 oC over 8 h
the isolated yield was improved to 85%.

2
Tetrahedron
corresponding aza-arene derivatives 4j, 4k and 4l, respectively,
in good yield (table 1).
We further focused on the synthesis of quinoline derived aza-
arene moieties. Towards this, 2-methylquinoline was reacted
with a series of aldehydes and melanonitrile to provide the
corresponding aza-arene derivatives 6a-6h in 78-89% yield
(Table 2). A similar kind of reactivity pattern was observed in the
case of 1 with various aldehydes. In addition, another derivative
of quinoline, 2-methyl-6-fluoroquinoline, was also reacted with a
variety of aldehydes, possessing electron-donating and electron-
withdrawing groups, providing the corresponding aza-arene
derivatives 6i-6o. Interestingly, the reaction also works well with
heterocyclic aldehydes, pyridine 3-carbaldehyde, furfuraldehyde
and thiophene 2-carbaldehyde, in presence of melanonitrile
providing the aza-arene derivatives 6p, 6q and 6r respectively.
These results indicate that, the one-pot aza-arene synthesis is
highly feasible in PEG-400 using 2-alkyl pyridine derivatives,
with aryl or heteroaryl aldehydes, and melanonitrile. It is also
worth to mention that, the halo substituted aza-arenes could be
further functionalized by using cross coupling reactions to obtain
a variety of highly substituted aza-arene moieties.
Scheme 1. One-pot synthesis of 2-substituted aza-arenes by PEG
mediated Knoeveanagel condensation through sp3 C-H
functionalization reaction.
After finding the optimized reaction conditions, the generality
of the reaction was evaluated by synthesizing a series of aza-
arene derivatives. Thus, reactions with substituted aldehydes
possessing halogens or alkyl groups proceeded smoothly to give
the corresponding aza-arene derivatives in good yield (4b-4g).
Interestingly, aldehydes having an electron withdrawing nitro
group reacted smoothly and provided the corresponding aza-
arene derivative 4h in high yield (92%) compared to the aldehyde
having an electron donating methyl (4g) or isopropyl (4i) group,
which provided the aza-arene derivative in comparatively lower
yield (82% and 80% respectively). Unfortunately, no reaction
was observed with electron rich aldehydes like anisaldehyde etc.
The generality of the reaction was further extended to aldehydes
derived from hetero aromatic compounds. Thus, pyridine-3-
carbaldehyde, pyridine-4-carbaldehyde and thiophene-2-
carbaldehyde in presence of 2,6-dimethyl pyridine and
malanonitrile, under the one-pot reaction conditions, provided the
Table 2. Synthesis of quinoline based aza-arene derivatives 6a-6r
produced via Scheme 1.
X
CHO
R
R
PEG-400
85 oC, 8h
NC
CN
+
+
X
CN
CN
CN
N
N
Table
1.
Synthesis
2-(2-(6-methylpyridin-2-yl)-1-
phenylethyl)malononitrile derivatives 4b–4l produced via
CN
5
2
3
R = H or F 6a-6r (yield)a
Br
CH3
Scheme 1.
X
CHO
PEG-400
85 oC, 8h
NC
CN
+
+
X
CN
CN
N
CN
CN
CN
N
N
N
6c, 80%
N
CN
CN
1
2b-2i
3
4b-4i (yield)a
6a, 81%
6b, 84%
NO2
F
Cl
Br
N
CN
CN
N
CN
N
N
CN
CN
CN
CN
CN
N
N
N
6d, 82%
6e, 89%
6f, 83%
CN
CN
CN
4b, 83%
4c, 84%
4d, 86%
O
S
F
Cl
CH3
CN
CN
CN
CN
CN
CN
N
N
N
Br
6g, 80%
6h, 78%
6i, 85%
Cl
CN
N
CN
CN
Br
CH3
N
N
CN
CN
CN
N
F
Br
CN
F
F
4e, 84%
4f, 85%
4g, 82%
N
CN
CN
CN
CN
N
N
CN
NO2
6j, 85%
6k, 80%
6l, 85%
F
F
NO2
CN
F
F
F
F
F
N
CN
CN
F
N
N
CN
CN
N
CN
CN
CN
CN
CN
N
N
CN
CN
, 92%
4h
, 80%
4i
, 85%
4j
, 90%
, 80%
, 85%
6o
6m
6n
N
N
S
O
S
F
CN
CN
CN
CN
CN
CN
CN
N
N
N
N
N
CN
CN
CN
, 86%
4k
4l, 78%
6p, 80%
6q, 82%
6r, 85%
a Yield refers pure and isolated products.
a Yield refers pure and isolated products.

3
4. (a) Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M. T. Org.
A proposed mechanistic pathway for the formation of aza-
arene derivatives is shown in scheme 2. One can visualize that
2,6-dimethyl pyridine will exist in an equilibrium with the
corresponding enamine 7 in PEG-400 solvent probably due to the
protonation of ring nitrogen. In the similar reaction conditions,
PEG-400 initiated knoevenagel condensation of benzaldehyde 2
and malononitrile 3 to provide the 2-benzylidenemalononitrile 9
via the intermediate 8. Michael addition of enamine 7 on to α,β-
unsaturated compound 9 facilitates the formation of aza-arene
intermediate 10 which further converts to the desired product 2-
(1-phenyl-2-(pyridin-2-yl)ethyl)malononitrile 4a (Scheme 2).
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Scheme 2. Proposed mechanism for the synthesis of aza-arene
derivatives.
In conclusion, an expeditious protocol for the synthesis of 2-
(2-(6-methylpyridin-2-yl)-1-phenylethyl)malononitrile
derivatives using PEG-400 as an eco-friendly, recyclable reaction
medium is developed. Notifyingly, the reaction doesn’t require
any additive or acid catalyst. The mild reaction conditions,
inexpensive reaction medium, operational simplicity and high
yields are the main advantages of this protocol. To the best of our
knowledge, the present protocol is the first report on the one-pot
Knoevenagel condensation followed by sp3 C-H functionalization
for the synthesis of aza-arene derivatives.
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Acknowledgments
R.M. thank University Grants Commission India (UGC-
SC/ST, PDF) for the financial support. V.D.K.R thank BRNS
(Sanction No. 37(2)/14/32/2014-BRNS) for fellowship.
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Supplementary Material
Supplementary data (experimental procedures, characteriza-
tion of compounds, and copies of NMR spectra) associated with
this article are available.
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4
Tetrahedron
Graphical Abstract
PEG-400 mediated sp3 C-H functionalization
of aza-arenes: an enroute to the synthesis of
2-(2-(6-methylpyridin/quinolin-2-yl)-1-
phenylethyl)malononitriles
Leave this area blank for abstract info.
Raghu Mallepalli,[a][b] Dinesh Kumar Reddy Vennam[a][b] and Ramu Sridhar Perali *[a]

5
Highlights:
ꢀ A one-pot protocol for the synthesis of
substituted aza-arenes is revealed.
ꢀ Functionalization of the Sp3 C-H of 2-alkyl
pyridines/quinolines is achieved
ꢀ The generality of the reaction was proved by
synthesizing 30 various aza-arene motifs
ꢀ PEG-400 as an eco-friendly and recyclable
reaction medium was developed
ꢀ The reaction doesn’t require any additive or
acid catalyst