Graphene oxide: A carbocatalyst for the one-pot multicomponent synthesis of highly functionalized tetrahydropyridines

Article abstract of DOI:10.1016/j.tetlet.2017.05.067

A simple, straightforward and efficient methodology is described for the synthesis of polysubstituted tetrahydropyridine via one-pot multicomponent reaction of β-ketoester, aldehyde and aniline in presence of catalytic amount of graphene oxide in acetonitrile. Graphene oxide is a versatile carbocatalyst and this is the first report on its application in a five component reaction. Good yield, usage of readily available starting material, operational simplicity, easy work-up and eco-friendly re-usable catalyst are the key features of this protocol.

Full text of DOI:10.1016/j.tetlet.2017.05.067

Accepted Manuscript
Graphene oxide: A carbocatalyst for the one-pot multicomponent synthesis of
highly functionalized tetrahydropyridines
Annah Gupta, Ramneet Kaur, Deepika Singh, Kamal K. Kapoor
PII:
S0040-4039(17)30657-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.05.067
TETL 48960
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
15 April 2017
17 May 2017
18 May 2017
Please cite this article as: Gupta, A., Kaur, R., Singh, D., Kapoor, K.K., Graphene oxide: A carbocatalyst for the
one-pot multicomponent synthesis of highly functionalized tetrahydropyridines, Tetrahedron Letters (2017), doi:
http://dx.doi.org/10.1016/j.tetlet.2017.05.067
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2
Graphical Abstract
Graphene oxide: A carbocatalyst for the one-pot
multicomponent synthesis of highly functionalized
tetrahydropyridines
Leave this area blank for abstract info.
Annah Gupta, Ramneet Kaur, Deepika Singh and Kamal K.
Kapoor*

1
Tetrahedron Letters
Graphene oxide: A carbocatalyst for the one-pot multicomponent synthesis of
highly functionalized tetrahydropyridines
Annah Guptaa , Ramneet Kaura, Deepika Singhb and Kamal K. Kapoora
aDepartment of Chemistry, University of Jammu, Jammu-180 006, India
bMedicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu-180001
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A simple, straightforward and efficient methodology is described for the synthesis of
polysubstituted tetrahydropyridine via one-pot multicomponent reaction of β-ketoester,
aldehyde and aniline in presence of catalytic amount of graphene oxide in acetonitrile.
Graphene oxide is a versatile carbocatalyst and this is the first report on its application in a five
component reaction. Good yield, usage of readily available starting material, operational
simplicity, easy work-up and eco-friendly re-usable catalyst are the key features of this protocol.
Available online
Keywords:
Graphene oxide
2009 Elsevier Ltd. All rights reserved.
Carbocatalyst
Multicomponent reaction
Tetrahydropyridine
Heterogeneous catalysis
One-pot reaction
 Corresponding author Tel.: +91-191-2453969;
fax: +91-191-2450014/2431365; e-mail: kamalkka@gmail.com

2
IRA400-Cl Resin/I2/KI,29 TiCl2.H2O,30 p-sulfonic acid
Pyridine scaffolds are of interest in organic and medicinal
chemistry due to the prevalence of their saturated and partially
saturated derivatives in numerous natural products such as NAD
nucleotides, pyridoxol (vitamin B6), pyridine alkaloids1 and
exhibit a plethora of biological properties such as antimalarial,
anti-microbial, anesthetic, anti-inflammatory, anticonvulsant,
antioxidant and antiparasitic.2 Despite the importance of pyridine
nucleus in pharmaceuticals, it also find its application in
agrochemistry3 (as herbicides, pesticides, fungicides) and in
supramolecular chemistry due to π-stacking ability.4
Tetrahydropyridine, in particular has been recognized as core
structure in some natural products and synthetic bioactive
molecules.5 Some of the bioactive tetrahydropyridine derivatives
are depicted in Figure 1. Arecoline, I is known to posses
stimulating effect owing to its agonistic influence on muscarinic
acetylcholine receptors,6 II is an aroma compound identified in
proline-containing foods such as Basmati rice, popcorn, bread
crust.7 Another tetrahydropyridine unit containing natural product
is Betanin III, a plant pigment, which is used as food additive8
and 4-[2-(4-Fluorophenyl)-4-(1,2,3,6-tetrahydropyridin-4-yl)-1H-
pyrrol-3-yl]pyridine(IV) has been reported to posses
proinflammatory protein inhibition activity.9 Droperidol and
Tazomeline are proven to be anti-emetic and antipsychotic agents
which are effective for the treatment of cognitive dysfunctional
diseases such as Alzheimer’s disease and Schizophrenia.10 The
role of tetrahydropyridine as inhibitor of farnesyl transferase11
and dihydroorotate dehydrogenase12 is also well documented.
Additionally, they can also act as precursor for the synthesis of
piperidine derivatives. Due to the broad spectrum of bioactivity
calix[n]arenes,31
acetic
acid,32
p-TSA,33
Y(NO3)3,34
La(NO3)3.6H2O,35 phenylboronic acid36 and zinc hydrogen
sulphate,37 ZrCl4.38
In our ongoing efforts on the synthesis of various heterocycles
39 and in pursuance of our experience with graphene oxide 40 as
eco-benign heterogeneous catalyst in three component reaction
for the synthesis of 1-amidoalkyl-2-naphthol and 1,2-dihydro-1-
arylnaphth[1,2-e][1,3]oxazin-3-one, we wished to probe its usage
in 5-component reactions. Herein, we present our successful
findings in one-pot five component reaction between β-ketoester,
two molecules of aldehyde and two molecules of substituted
aniline using graphene oxide as eco-compatible catalyst to yield
highly functionalized tetrahydropyridine in good to excellent
yields. To the best of our knowledge, this is the first report on the
application of Graphene oxide in a five-component reaction.
Owing to large surface area, ease in synthesis, inertness and
bio-compatibility, graphene oxide has proven to be a promising,
efficient and economical carbocatalyst41 in organic synthesis. A
number of oxygen containing functionalities such as epoxy,
hydroxyl and carboxyl groups are present on the surface of
graphene oxide (Figure 2) which are responsible for its acidic
nature42 and oxidising properties.43
COOH
COOH
HOOC
OH
COOH
(analgesic,13
hyperglycaemic,14
anti
malarial15),
O
O
O
O
O
HOOC
HO
tetrahydropyridine derivatives became attractive synthetic target
for medicinal and organic chemists. As a result, a variety of
methodologies have been developed for their synthesis such as
proline mediated cascade Mannich type intramolecular
cyclization,16 reaction of dihydropyran with anilines,17 amine
catalysed annulations of Morita-Baylis-Hillman acetate with
1,3-azadienes.18 These methodologies suffer from one or other
disadvantages such as multistep synthetic sequence, requirement
of expensive reagents or catalysts, etc.
HO
O
COOH
COOH
O
O
OH
COOH
COOH
Figure 2: Structural model of graphene oxide
We envisaged our study by choosing methylacetoacetate
(1mmol), 4-chlorobenzaldehyde (2mmol) and aniline (2mmol) as
model substrates for optimization studies. Methylacetoacetate 1
(1 mmol) and aniline 2 (2 mmol) were heated at 120C in
presence of 50 mg (43 wt% w.r.t β-ketoester) of graphene oxide
(prepared by modified Hummers method44 and characterized by
IR spectrum) for 30 min under solvent free condition to form
the enamine intermediate followed by the addition of 4-
chlorobenzaldehyde 3 (2 mmol). The reaction mixture was
further heated till the complete formation of product 4d (2h,
TLC, 65% yield). In order to improve the yield of the reaction
various solvents and catalyst loading were screened and the
results are depicted in Table 1. Among the various tested
mediums (CH3CN, EtOAc, 1,4-Dioxane, THF ) and scanned
catalyst loading (10, 20, 30, 40 mg), it was found CH3CN in
combination with 30 mg (26 wt% w.r.t β-ketoester) of catalyst
gave the best results.
Figure 1: Few bioactive tetrahydropyridine derivatives
In the perspective of green chemistry, the main challenge for
organic chemists is to develop synthetic routes which allow
selective access to molecular scaffolds with structural diversity
under eco-benign conditions. In this context, multicomponent
reactions (MCRs) have evoked much attention and proven to be
an improved alternative in organic synthesis due to its selectivity,
atom and synthetic step economy. In recent years, the synthesis
of highly functionalized tetrahydropyridines have been reported
via five component reaction involving one molecule of β-
ketoester, two molecules of aldehyde and two molecules of
substituted aniline in presence of various catalysts such as
InCl3,19 LaCl3.7H2O,20 bromodimethylsulfonium bromide
Table 1: Optimization of reaction conditions
Yieldb (%)
S.No.
Solvent
Amount of
catalyst in mga
50 (43)
(BDMS),21
iodine,22
BF3/SiO2,23
ZrOCl2.7H2O,24
-
65
tetrabutylammonium tribromide (TBATB),25 tartaric acid,26
1
cerium ammonium nitrate,27 α-Fe2O3-BIMtribromide,28 amberlite

3
CH3CN
EtOAc
50 (43)
50 (43)
50 (43)
50 (43)
-
94
33
38
42
18
60
73
94
94
anilines
ethylacetoactate)
tetrahydropyridines (4a-r) in good to excellent yields (Table 2).
and
β-ketoesters
to provide
(methylacetoacetate
and
2
3
the corresponding
1,4-Dioxane
THF
4
In analogy with reported mechanisms,31,32,45 the following
mechanism is proposed to explain the formation of product
(Scheme 1). Graphene oxide acts as an acid catalyst and
facilitates the respective formation of enamine (5) and imine (6)
from aniline, β-ketoester and aldehyde. Next, intermolecular
Mannich type reaction occur between 5 and 6 to yield
intermediate 7, which on further condensation with second
5
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
6
10 (9)
20 (17)
30 (26)
40 (35)
7
8
molecule of aldehyde generates 8. Intermediate
8
on
tautomerization, followed by intermolecular Mannich type
9
reaction affords the product tetrahydropyridines (4).
10
To establish the mechanistic integrity, enamine intermediate
(methyl-3-(phenylamino)but-2-enoate) was isolated in one of the
experiment and characterized by spectral data and its comparison
with the literature reports.46 The enamine was further reacted with
1 eq. each of aniline and aldehyde to realize the formation of the
desirable product.
a wt.% w.r.t β-ketoester is given in parenthesis
b Isolated Yield
With these optimized conditions in hand, the scope and
generality of this five component reaction was investigated. The
reaction was successful with various substituted aldehydes,
Table 2: Substituted tetrahydropyridines synthesized by the reaction of β-ketoester substituted aldehyde, and anilines
4b
4a
4d
4c
(92%, 3 h)
(90%, 3.5 h)
(94%, 3 h)
(92%, 3.5 h)
4e
4f
4g
(89%, 4 h)
4h
(86%, 3.5 h)
(91%, 3.5 h)
(91%, 3 h)

4
4i
4k
(90%, 3h)
4l
4j
(91%, 3h)
(87%, 4 h)
(90%, 3.5 h)
4n
4m
(88%, 4 h)
4o
4p
(92%, 3.5 h)
(90%, 3.5 h)
(87%, 4 h)
4q
4r
(88%, 3.5 h)
(89%, 4 h)

5
Scheme 1. Plausible mechanism for one pot synthesis of functionalized tetrahydropyridine
Since graphene oxide can be recovered from the reaction
mixture simply by filtration, it was further tested for its
reusability. Catalyst obtained from the reaction of
methylacetoacetate, aniline and 4-chlorobenzaldehyde was
washed with warm acetonitrile and reused in a series of five
consecutive runs and results are shown in Figure 3. As it is
evident from the results that the catalyst is reusable upto five
runs without significant loss of activity. The IR spectra of the
recovered catalyst after 1st, 3rd and 5th runs were compared with
the catalyst before the reaction and no significant changes in
the diagnostic bands were noticed.
In conclusion, an efficient protocol has been developed for
the construction of highly functionalized tetrahydropyridines
by employing catalytic amount of graphene oxide via one-pot
multicomponent reaction of β-ketoester, substituted aldehyde,
anilines. Graphene oxide is eco-benign and heterogeneous in
nature, recoverable and reusable without any significant loss in
catalytic activity. The advantages of this protocol are good
yield, usage of readily available starting material, operational
simplicity, easy work-up and eco-friendly catalyst.
Acknowledgement
The authors are thankful to Department of Chemistry,
University of Jammu for providing all necessary facilities and
Department of Science and Technology, Government of India,
New Delhi for NMR facility under PURSE and INSPIRE
fellowship [AG].
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47. General procedure for the synthesis of highly
functionalized tetrahydropyridines: A mixture of β-ketoester
(1 mmol) and substituted anilines (2 mmol) in acetonitrile (10
ml) in presence of graphene oxide (30 mg, 26 wt.%) was stirred
for 30 min under reflux, followed by addition of aldehyde (2
mmol). The resultant mixture was continued stirring under
refluxing solvent till the completion of reaction [TLC; Table 2].
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Highlights
•
•
•
Works well with various substituted aldehydes, anilines and β-ketoesters.
Graphene oxide is recoverable and reusable.
Highly substituted tetrahydropyridines are obtained in high yields.