Cyanuric chloride catalyzed metal-free mild protocol for the synthesis of highly functionalized tetrahydropyridines

Article abstract of DOI:10.1016/j.tetlet.2017.08.074

An environmentally benign, facile and elegant synthetic approach for the convenient access of a series of diverse 2,6-diaryl-tetrahydropyridine-3-carboxylates via a one-pot, pseudo five-component condensation of ethyl acetoacetate, anilines and aromatic aldehydes under mild reaction conditions has been described. This domino strategy allows rapid cyclization in the presence of 10 mol% of cyanuric chloride as a source of hydrochloric acid to afford the desired target skeletons in excellent yields. The present protocol offers prominent advantages of simple operational procedure, metal-free organocatalyst, practically robust and extensive substrate scope.

Full text of DOI:10.1016/j.tetlet.2017.08.074

Accepted Manuscript
Cyanuric chloride catalyzed metal-free mild protocol for the synthesis of highly
functionalized tetrahydropyridines
Rathinam Ramesh, Subramani Maheswari, Mani Arivazhagan, Jan Grzegorz
Malecki, Appaswami Lalitha
PII:
S0040-4039(17)31096-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.08.074
TETL 49264
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
13 July 2017
26 August 2017
29 August 2017
Please cite this article as: Ramesh, R., Maheswari, S., Arivazhagan, M., Malecki, J.G., Lalitha, A., Cyanuric chloride
catalyzed metal-free mild protocol for the synthesis of highly functionalized tetrahydropyridines, Tetrahedron
Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.08.074
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Cyanuric chloride catalyzed metal-free mild
protocol for the synthesis of highly
functionalized tetrahydropyridines
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Rathinam Ramesh, Subramani Maheswari, Mani Arivazhagan, Jan Grzegorz Malecki, Appaswami Lalitha*

1
Tetrahedron Letters
journal homepage: www.els evier.com
Cyanuric chloride catalyzed metal-free mild protocol for the synthesis of highly
functionalized tetrahydropyridines
Rathinam Ramesha, Subramani Maheswaria, Mani Arivazhagana, Jan Grzegorz Maleckib and Appaswami
Lalithaa, ∗
aDepartment of Chemistry, Periyar University, Periyar Palkalai Nagar, Salem-636011, Tamil Nadu, India
bDepartment of Crystallography, University of Silesia, Szkolna 9, 40-006 Katowice, Poland
ARTICLE INFO
ABSTRACT
Article history:
Received
An environmentally benign, facile and elegant synthetic approach for the convenient access of a
series of diverse 2,6-diaryl-tetrahydropyridine-3-carboxylates via a one-pot, pseudo five-
component condensation of ethyl acetoacetate, anilines and aromatic aldehydes under mild
reaction conditions has been described. This domino strategy allows rapid cyclization in the
presence of 10 mol% of cyanuric chloride as a source of hydrochloric acid to afford the desired
target skeletons in excellent yields. The present protocol offers prominent advantages of simple
operational procedure, metal-free organocatalyst, practically robust and extensive substrate
scope.
Received in revised form
Accepted
Available online
Keywords:
Cyanuric chloride
Pseudo five-component reaction
Tetrahydropyridines
Green synthesis
2009 Elsevier Ltd. All rights reserved.
In recent years, the chemical industry and academia have been
functioning together in order to facilitate the newer as well as
environmentally benign catalysts and solvents.1,2 The ultimate
intend is to diminish significantly the hazards associated with
metal salts and traditional solvents and replacing them with
efficient non-toxic alternatives. The explorations of economically
viable and readily existing catalysts that create organic
transformations in facile route are constantly an attractive
approach in modern organic and medicinal chemistry. In this
regard, cyanuric chloride (2,4,6-trichloro-1,3,5-triazine) has been
accounted as an inexpensive, frequently accessible, low toxic and
less corrosive reactants than other similar ones. Owing to their
valuable specifics, quite numbers of researchers have been
deliberated well with TCT as an efficient catalyst.3-8
Multicomponent reactions (MCRs) are powerful and highly
valuable synthetic tool for the construction of complex and novel
organic skeletons with the limited synthetic steps. Simplicity
fused with operational procedure, low costs, minimization of
chemical wastes and time, high degrees of atom economy and
environmental friendliness are the immense advantages over
conventional step by step synthetic strategies.23,24 Following our
continuous efforts devoted to the synthesis of diverse
heterocyclic compounds with the abets of green solvents or
catalysts,25-31 herein we described an efficient protocol for the
convenient access of some novel 2,6-diaryl-tetrahydropyridine-3-
carboxylates via a one-pot, pseudo five-component reaction using
cyanuric chloride (TCT) as a catalyst under mild reaction
conditions.
Tetrahydropyridine like compounds are extensively emerging
as potent building blocks for numerous natural as well as
medicinally privileged synthetic scaffolds.9-11 Fascinatingly,
some of the synthetic methods have been documented in
literature for the access of THPs with diverse statics due to their
pronounced pharmaceutical usage as, anti-HIV,12 anticancer,13
antihistamic,14 antimicrobial,15 antimalarial,16 antiinflammatory17
and anti-insecticidal18 agents. In addition, a few of these
derivatives have been emerged as potent inhibitors of farnesyl
transferase,19 dihydroorotate dehydrogenase20 and MAO-based
mechanism in Parkinson's diseases.21,22
To begin with, stoichiometric amounts of 4-fluoroaniline (1a),
ethyl acetoacetate (2) and 4-chlorobenzaldehyde (3b) were taken
as model substrates in ethanol for optimization studies. Initially,
the reaction was performed without any catalyst at reflux
temperature for about 3 h. Where, no tetrahydropyridine
derivative (4b) was produced. Next, the model reaction was
conducted in the presence of sulfamic acid (20 mol%) under
identical reaction conditions. In this case, the desired THP
derivative was produced in poor yield (47%) after 2 h. In order to
get the better outcome of the reaction various catalysts were
screened such as, trifluororacetic acid, p-toluenesulfonic acid and
cyanuric chloride (20 mol% each) and the results are summarized
in Table 1. Among the catalysts tested, it was clear that TCT in
———
∗ Corresponding author. Tel.: +91-427-234-5271; fax: +91-427-234-5124; e-mail: lalitha2531@yahoo.co.in

2
Tetrahedron Letters
ethanol under reflux condition provided the best results (96%
yield in 15 min).
electron-withdrawing (Table 2, entries 2, 3 and 9) or electron-
donating substituents (Table 2, entries 4, 5, 6, 7, 8 and 10) in
various positions reacted smoothly to afford the corresponding
2,6-diaryl-tetrahydropyridine-3-carboxylates (4b-j) in good to
excellent yields (89-96%, Table 2, entries 2-10). Finally, the
synthesized polyfunctionalized tetrahydropyridine derivatives
were confirmed by their melting points, 1H and 13C NMR spectral
analyses.
Table 2. Cyanuric chloride catalyzed pseudo five-component
synthesis of 2,6-diaryl-tetrahydropyridine-3-carboxylatesa
Time
(min)
Yieldb
(%)
Scheme 1. Synthesis of 2,6-diaryl-tetrahydropyridine-3-carboxylate
derivatives
Entry
R
R’
Product
1
2
3
4
5
6
7
4-F
4-F
4-F
4-F
4-F
4-F
4-F
H
4a
4b
4c
4d
4e
4f
20
15
15
12
35
45
60
90
95
96
91
93
89
91
Encouraged by this observation, we next examined the
reaction with the use of a variety of polar protic and aprotic
solvents such as, methanol, acetonitrile, 2-propanol and
tetrahydrofuran as reaction medium. The results furnished in
Table 1 revealed that, ethanol would be the more desirable
solvent for the better outcome of this multicomponent reaction.
We have checked the feasibility of our methodology with
different percentage of TCT (5, 10, 15 and 20 mol%) as catalyst
in ethanol at reflux temperature (Table 1, entries 4, 5, 6 and 7).
The reaction proceeded smoothly in the presence of 10 mol% of
TCT and offered the desired 2,6-diaryl-tetrahydropyridine-3-
carboxylate (4b) in excellent yield (Table 1, entry 6). In our quest
to fix the optimal temperature for the best results, the model
reaction was carried out at ambient conditions and it was found
that the reaction was sluggish and provided poor yield of 4b
(29%) even after 8 h. With these findings, we have selected 10
mol% of TCT in ethanol at reflux temperature as a suitable
strategy for the preparation of tetrahydropyridine derivatives in
an attractive manner.
4-Cl
4-NO2
4-CH3
4-OCH3
4-OH
3,4-OCH3
4g
4-OH,3-
OCH3
8
4-F
4h
60
90
9
4-F
3-NO2
3-OH
4i
4j
20
40
30
20
20
40
45
60
55
93
89
89
92
94
88
90
87
90
10
11
12
13
14
15
16
17
4-F
4-CH(CH3)2
4-CH(CH3)2
4-CH(CH3)2
4-CH(CH3)2
4-CH(CH3)2
4-CH(CH3)2
4-CH(CH3)2
H
4k
4l
4-Cl
4-NO2
4-CH3
4-OCH3
4-OH
4m
4n
4o
4p
4q
Table 1. Effect of catalyst and solvent on the synthesis of
compound 4ba
Time
(min)
Yieldb
(%)
Entry
Catalyst
Solvent
3,4-OCH3
1
2
NH2-SO3H (20 mol%)
CF3COOH (20 mol%)
p-TSA (20 mol%)
TCT (20 mol%)
TCT (15 mol%)
TCT (10 mol%)
TCT (5 mol%)
EtOH
EtOH
120
90
47
69
54
96
95
95
82
87
81
74
58
4-OH,3-
OCH3
18
4-CH(CH3)2
4r
60
88
19
20
21
22
23
24
25
26
4-CH(CH3)2
4-CH(CH3)2
4-Cl
3-NO2
3-OH
4-Cl
4s
4t
25
60
20
20
35
30
30
60
91
88
93
95
89
91
88
85
3
EtOH
120
15
4
EtOH
4u
4v
4w
4x
4y
4z
5
EtOH
15
4-Br
4-Cl
6
EtOH
15
4-OCH3
4-F
4-Cl
7
EtOH
45
2-NO2
2-Cl
8
TCT (10 mol%)
TCT (10 mol%)
TCT (10 mol%)
TCT (10 mol%)
MeOH
CH3CN
(CH3)2CHOH
THF
30
4-F
9
60
4-F
2-OH
10
11
60
aReaction conditions: ethyl acetoacetate (2.0 mmol), 4-substituted aniline (4.0
mmol), aromatic aldehyde (4.0 mmol) and cyanuric chloride (10 mol%) in
ethanol (10 ml) stirred at 80 °C.
120
No
Reaction
12
-
EtOH
180
bIsolated yields.
aReaction conditions: ethyl acetoacetate (2.0 mmol), 4-fluoroaniline (4.0
mmol), 4-chlorobenzaldehyde (4.0 mmol) and catalyst in different solvent (10
ml) stirred at reflux temperature.
1
In the H NMR spectrum of compound 4b as a representative
example, the ethoxy (-OCH2CH3) protons appeared as a triplet at
δ 1.35 ppm (J = 7.2 Hz) and two multiplets at δ 4.23-4.38 ppm (J
= 7.2 Hz). A couple of doublets observed at δ 2.66 ppm (J = 14.8
Hz) and δ 2.92ppm (J = 15.2 Hz) corresponds to the methylene
(CH2) protons of the THP ring. One of the benzylic methine (-
CH) proton of the THP ring showed a singlet at δ 5.33 ppm and
another methine proton (-CH) showed a singlet at δ 6.17 ppm
respectively. The aromatic protons were observed as multiplets in
the range at δ 6.32-7.39 ppm. The NH proton was observed as a
singlet at δ 10.15 ppm clearly indicating that it was connected to
bIsolated yields.
Next, we turned our interest to explore the generality and
scope of the present pseudo five-component reaction with the
optimized conditions by using diverse aryl aldehydes (3a-j)
bearing different functional groups. The unsubstituted
benzaldehyde (3a) underwent the reaction efficiently and gave
the desired product 4a in 90% yield (Table 2, entry 1). The
results depicted in Table 2 revealed that the aldehydes possessing

3
the vicinal carbonyl group (-C=O) via a intramolecular H-bond
formation. In the 13C NMR spectrum, the carbonyl carbon (-
C=O) showed a peak at δ 165.3 ppm and the aromatic carbons
were observed in the range at δ 114.8-148.8 ppm respectively. In
addition, the methylene and methine carbons showed signals at δ
52.0-62.6 ppm. Specifically, the mono crystal structure of
compound 4d was further confirmed by X-ray diffraction
analysis (Figure 1). With these spectral evidences we
unambiguously confirmed the structure of the synthesized
compounds.
The possible mechanism that suits for the synthesis of
tetrahydropyridines has been outlined in Scheme 2. Initially, the
cyanuric chloride reacts with atmospheric moisture to give three
molecules of HCl with cyanuric acid as a by-product. The
starting substrates 4-fluoroaniline (1a) and ethyl acetoacetate (2)
reacted together to afford the β-enaminone intermediate (I) which
was assisted by the HCl generated from TCT. In the next step,
the 4-chlorobenzaldehyde (3b) condensed with another molecule
of 4-fluoroaniline (1a) gives the desired Schiff’s base (II). Then
the enaminone (I) and the Schiff’s base (II) undergo
intermolecular Mannich reaction in the presence of H+ to afford
the intermediate III. Here, one more molecule of activated
aldehyde (3b) reacted with III to offer the intermediate IV by the
removal of water molecule. Then, the intermediate IV undergoes
tautomerization to generate the more reactive intermediate V,
which subsequently undergoes intramolecular Mannich reaction
to give the functionalized piperidine (VI) skeleton. Finally, the
intermediate VI tautomerizes under acidic condition to afford the
polyfunctionalized tetrahydropyridine (4b) as a sole product.
The efficacy of TCT is compared with the earlier reported
catalytic methods by the chemical yield, catalyst quantity and
reaction time. Besides, this protocol works adequately on gram
scale (50 mmol) for the preparation of compound 4b (25.62g,
88%) as representative reaction. The results revealed (Table 3,
Entry 10), that 10 mol% cyanuric chloride is most effective for
the better outcome of the present synthetic approach and this may
opened
polyfunctionalized THPs in gram scale production.
a
new avenue for the efficient access of
Table 3. Comparison of efficacy of TCT with reported
catalytic methods
Time
(min)
Yield
(%)
Entry
Catalyst
Conditions
1
2
Graphene oxide
CAN (15 mol%)
CH3CN, Reflux
CH3CN, RT
210
9132
6833
2100
[Dsbim]Cl (10
mol%)
3
Solvent-free, 80 °C
30
9634
4
5
Fe@Si-Gu-Prs
ZnO NPs
Solvent-free, RT
Solvent-free, RT
25
9135
8936
180
2,6-PDCA (10
mol%)
6
7
8
MeOH, RT
Solvent-free, RT
EtOH, 40 °C
480
30
8037
9138
8339
NFS-PWA
[Bmim-G-
(SO3H)4]+[HSO4]-
Figure 1. ORTEP of compound 4d (CCDC 1561955)
600
After the execution of our strategy in a successive manner, we
further enlarging the versatility of this pseudo multi-component
approach by using 4-isopropylaniline (1b) as an alternative for 4-
fluoroaniline (1a) under the optimal reaction conditions. The
results are also furnished in Table 2 (Entries 11-20). The model
experiment by the employment of benzaldehyde (3a) was also
found to be appropriate for the pseudo-reaction and provided the
corresponding product (4k) in 89% yield (Table 2, entry 11). It is
more clear from the results outlined in Table 2 that, all the
studied reactions proceeded very smoothly and aldehydes bearing
substituents in different positions were also well tolerated to
provide the corresponding targets 4(l-t) in moderate to good
yields (87-94%). In addition, the scope of this methodology was
further explored to the other aryl amines 1(c-d) and ortho-
substituted benzaldehydes (nitro, chloro and hydroxy) proved to
be fine substrates. Pleasingly, the reactions were accomplished
effectively under similar reaction conditions affording the desired
products 4u-4z in good yields (Table 2, entries 21-26). The
structural skeleton of the synthesized tetrahydropyridine
derivatives were in fine concurrence with the spectral data.
CoFe2O4 MNPs (8
mol%)
9
H2O:EtOH, 120 °C
EtOH, Reflux
60
15
9440
95This
10
TCT (10 mol%)
work
Furthermore, the employment of TCT as a catalyst with the
production of cyanuric acid as by-product reveals the lack of
ability in catalytic recycle and it can be removed by washing with
water. In order to find the catalytic activity of in-situ cyanuric
acid, we have conducted the reaction between 4-fluoroaniline
(1a), ethyl acetoacetate (2) and 4-chlorobenzaldehyde (3b) with
10 mol % of cyanuric acid as a catalyst and observed that the
reaction could not be completed even after 8 h.
Scheme 2. Plausible mechanistic steps in the formation of
compound 4b

4
Tetrahedron Letters
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candidates corroborating as natural and drug like molecules. It is
the more practical and shortest route for the syntheses of THPs
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In conclusion, we have introduced the cyanuric chloride
catalyzed, an efficient, green and practical approach for the
preparation of 2,6-diaryl-tetrahydropyridine-3-carboxylates
through the pseudo five-component reaction of ethyl
acetoacetate, anilines and aryl aldehydes under mild reaction
conditions. Owing to the exemplary synthetic versatility, this
protocol offers some other advantages such as, use of
organocatalyst, simple starting substrates, shorter reaction times
and good chemical yields. The proficient catalytic activity of the
TCT in this cyclocondensation reaction will definitely
accumulate to the already existing synthetic methodologies for
gram scale productions which make the present domino process
more convenient and eco-friendly.
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R. Ramesh gratefully thank DST-Inspire Fellowship, New
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Supplementary Material
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5
ꢀ Cyanuric chloride (TCT) is a stable, inexpensive
and easily accessible reagent
ꢀ High-yielding multicomponent reaction under
mild conditions
ꢀ Easier work-up method that is environmentally
benign and can be readily scaled-up
ꢀ Structures were also confirmed by single crystal
X-ray diffraction