Facile one-pot multicomponent synthesis of highly functionalized tetrahydropyridines using thiamine hydrochloride as an organocatalyst

Article abstract of DOI:10.1080/00397911.2020.1731756

Thiamine hydrochloride (VitB₁) has been found to be an efficient catalyst for the multicomponent synthesis of highly functionalized tetrahydropyridines from the reaction of β-ketoester, aromatic aldehydes and anilines. VitB₁ is easily available, cheap, and eco benign.

Full text of DOI:10.1080/00397911.2020.1731756

Synthetic Communications
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Facile one-pot multicomponent synthesis of highly
functionalized tetrahydropyridines using thiamine
hydrochloride as an organocatalyst
Sandeep Singh, Annah Gupta & Kamal K. Kapoor
To cite this article: Sandeep Singh, Annah Gupta & Kamal K. Kapoor (2020): Facile one-pot
multicomponent synthesis of highly functionalized tetrahydropyridines using thiamine hydrochloride
as an organocatalyst, Synthetic Communications, DOI: 10.1080/00397911.2020.1731756
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https://doi.org/10.1080/00397911.2020.1731756
Facile one-pot multicomponent synthesis of highly
functionalized tetrahydropyridines using thiamine
hydrochloride as an organocatalyst
Sandeep Singh, Annah Gupta, and Kamal K. Kapoor
Department of Chemistry, University of Jammu, Jammu, India
ABSTRACT
ARTICLE HISTORY
1
Thiamine hydrochloride (VitB ) has been found to be an efficient
Received 14 November 2019
catalyst for the multicomponent synthesis of highly functionalized
tetrahydropyridines from the reaction of b-ketoester, aromatic alde-
KEYWORDS
hydes and anilines. VitB is easily available, cheap, and eco benign.
1
b-Ketoester; tetrahydropyri-
dine multicomponent;
thiamine hydrochloride;
GRAPHICAL ABSTRACT
VitB
1
Introduction
[
1]
Pyridines are privileged structural motifs of large number of natural products such as
NAD nucleotides, pyridoxol (vitamin B ), pyridine alkaloids and compounds
6
[
1]
[2]
displaying applications in medicinal chemistry,
supramolecular chemistry,
and
[
3]
agrochemistry.
Tetrahydropyridine moiety, in particular, is abundant in various natural as well as
[
4,5]
synthetic bioactive molecules
which exhibit a plethora of biological properties such
[
6]
[7]
[8]
[9]
[10]
as analgesic, hyperglycemic, antimalarial, nicotinic, anticonvulsant,
and anti-
[
11]
influenza.
Some of the naturally occurring and bioactive tetrahydropyridine deriva-
tives are depicted in Figure 1.
Owing to the biological, pharmacological and synthetic importance of tetrahydropyri-
dines, several protocols have been developed for their synthesis such as proline assisted
[
12]
cascade Mannich type intramolecular cyclization,
reaction of dihydropyran with ani-
[
13]
[14]
lines, and annulations of Morita–Baylis–Hillman acetate with 1,3-azadienes.
Among the other methods known in literature, the most widely used one is one-pot
multicomponent condensation of aldehyde, aniline, and b-ketoester in the presence of
CONTACT Kamal K. Kapoor
kamalkka@gmail.com
Department of Chemistry, University of Jammu, Jammu, India
Supplemental data for this article can be accessed on the publisher’s website.
ß 2020 Taylor & Francis Group, LLC

2
S. SINGH ET AL.
Figure 1. Few naturally occurring and bioactive tetrahydropyridine derivatives.
[
15–22]
[23–25]
[26,27]
[28]
Lewis acids,
organic acids,
ionic liquids,
and organocatalyst.
Most of
these methods suffer from one or more shortcomings like poor yields, non-sustainabil-
ity, longer reaction times, expensive or toxic catalyst, etc. In continuation of our efforts
toward the development of efficient and environmentally friendly synthetic methods in
[
29–32]
organic synthesis,
we wished to explore the effect of VitB as a catalyst for the
1
synthesis of tetrahydropyridines.
Thiamine hydrochloride (VitB ), being nontoxic, cheap, easy to handle and its
1
[
33]
[34,35]
compatibility in water and air
has attracted a great intention of chemists.
VitB1
has been employed as a catalyst for the one-pot multicomponent synthesis of
[
36–39]
various heterocyclic compounds,
such as naphthol[1,2-e][1,3]oxazine-3-ones,
pyrido[2,3-d]pyrimidine-6-carbonitriles, benzo[4,5]imidazo[1,2-a]pyrimidine,[1,2,4]tri-
zolo[1,5-a]pyrimidine, tetrahydrobenzo[b]pyran derivatives, apart from its usage as a
catalyst in organic transformations such as Knoevenagel condensation, Michael addition
[
40,41]
and cyclization.
Multicomponent reactions are appreciated for creating diverse
[
42,43]
scaffolds of heterocycles, atom economy, low waste and high yields.
Results and discussion
To begin with, a mixture of methyl acetoacetate (1 mmol), aniline (2 mmol), and 4-
methoxybenzaldehyde (2 mmol) was heated in 10 mL ethanol/water (9:1) in the presence
of 20 mol% of Vit B , the desired product was obtained, albeit in low yield (30%).
1
Further replacing the ethanol/water with other solvents (ethanol, water, CH CN, 1,4-
3
dioxane, THF) did not result in any improvement in yield of the product. In another
set of experiment, a mixture of methyl acetoacetate (1 mmol) and aniline (2 mmol) was
heated in ethanol/water in the presence of 20 mol% of Vit B for 30 min, followed by
1
addition of 4-methoxybenzaldehyde (2 mmol). To our delight, significant improvement
in the (91% yield) was noticed. Altering the amount of catalyst to 10, 30, and 50 mol%
did not prove beneficial in the above reaction. Among the various tested mediums and

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Table 1. Optimization of reaction condition.
Yield (%)
Catalyst
(mol%)
S. No.
Solvent
Condition A
Condition B
1
2
3
4
5
6
7
8
9
Ethanol/water (9:1)
Ethanol
Water
CH CN
3
1,4-Dioxane
20
20
20
20
20
20
10
30
50
30
25
20
22
15
19
17
30
30
91
78
69
72
55
62
79
91
88
THF
Ethanol/water (9:1)
Ethanol/water (9:1)
Ethanol/water (9:1)
scanned catalyst loadings, it was found that ethanol/H O (9:1) in combination with
2
20 mol% of catalyst gave the best results (Table 1).
With these optimized conditions in hand, the scope and generality of this five-com-
ponent reaction was investigated. The reaction was successful with various substituted
aromatic aldehydes, anilines and b-ketoesters (methylacetoacetate and ethylacetoactate)
to provide the corresponding tetrahydropyridines 4 in good to excellent yields
(
Table 2).
[
37,44]
In analogy with reported mechanisms,
the following mechanism is proposed to
explain the formation of product (Scheme 1). Vitamin B acts as an acid catalyst and facili-
1
tates the respective formation of enamine (5) and imine (6) from aniline, b-ketoester, and
aldehyde. Next, intermolecular Mannich type reaction occurs between 5 and 6 to yield inter-
mediate 7, which on condensation with second molecule of aldehyde generates 8.
Intermediate 8 on tautomerization, followed by intramolecular Mannich type reaction
affords the product tetrahydropyridines 4.To support the mechanism described herein,
intermediate 5 was isolated, characterized and was made to react with benzylidine aniline,
under the similar reaction conditions to realize the formation of the desired product.

4
S. SINGH ET AL.
Table 2. Substituted tetrahydropyridines synthesized by the reaction of
b-ketoester substituted aldehyde and anilines.
4
a
4
c
(
93%, 3.5 h)
4d
91%, 3 h)
(
91%, 3.5 h)
4
b
(
(90%, 3.5 h)
4
e
4f
4
g
4h
(
88%, 4 h)
(89%, 3.5 h)
(
93%, 3.5 h)
(91%, 3 h)
4
j
4k
4l
4
i
(90%, 3.5 h)
(88%, 3.5 h)
(88%, 4 h)
(
92%, 3.5 h)
4
m
4n
4o
4
p
(
88%, 3 h)
(92%, 4 h)
(90%, 4 h)
(89%, 4 h)
4
q
4r
(
87%, 4 h)
(88%, 4.5 h)

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Scheme 1. Plausible mechanism for one-pot synthesis of functionalized tetrahydropyridine.
Experimental
General
All the experiments were performed in an oven-dried glass apparatus. All the commer-
cially available reagents were purchased from Aldrich and were used without further
ꢀ
purification. Melting points ( C) were measured in open glass capillaries using Perfit
melting point apparatus and are uncorrected. The progress of reaction was monitored
using thin-layer chromatography (TLC) using silica gel pre-coated aluminum sheets (60
F254, Merck). The crude products were purified by recrystallization with ethanol.
Visualization of spots was effected by exposure to ultraviolet light (UV) at 365 nm and
254 nm, iodine vapors and 2% 2,4-dinitrophenylhydrazine in methanol containing few
drops of H SO , draggendroff reagent, and anisaldehyde reagent. Solvents used in puri-
2
4
13
fication were distilled prior to use. 1H and C NMR were recorded on Bruker AC400

6
S. SINGH ET AL.
1
13
spectrometer operating at 400 MHz for H and 100 MHz for C with tetramethylsilane
TMS) as an internal standard. The chemical shifts are expressed in d (ppm) downfield
(
1
3
from TMS. All the C NMR spectra are proton decoupled. J values are given in Hertz
(
1
Hz). The abbreviations s, d, dd, t, q, and m in H NMR spectra refer to singlet, doub-
let, doublet of doublet, triplet, quartet, and multiplet, respectively. Solvents were
removed using Heidolph rotary evaporator.
Procedure for the synthesis of methyl-2,6-bis(4-methoxyphenyl)-1-phenyl-4-
(phenylamino)-1,2,5,6-tetrahydropyridine-3-carboxylate (4c)
A mixture of aniline(2 mmol) and methylacetoacetate (1 mmol) and VitB (20 mol%)was
1
heated in 10 mL ethanol/H O (9:1) at reflux. After 30 min, complete disappearance of
2
methylacetoacetate was noticed and at this point,4-methoxy benzaldehyde (2 mmol) was
added and heating was continued further for 3 h. Then the reaction mixture was poured
in ice-cold water and the precipitates obtained were filtered and recrystallized from
ethanol to yield the pure product.
Methyl-2,6-bis(4-methoxyphenyl)-1-phenyl-4-(phenylamino)-1,2,5,6-
tetrahydropyridine-3-carboxylate (4c)
1
White solid. M.P: 177–179 C [Lit. M.P: 178–180 C] H NMR (400 MHz, CDCl ) d
3
1
0.30 (s, 1H), 7.25 (d, J ¼ 8.2 Hz, 2H), 7.16 ꢁ 7.06 (m, 7H), 6.84 (d, J ¼ 8.2 Hz, 4H), 6.63
(
t, J ¼ 7.4 Hz, 1H), 6.56 (d, J ¼ 8.2 Hz, 2H), 6.39 (d, J ¼ 6.5 Hz, 3H), 5.12 (s, 1H), 3.95 (s,
3
1
1
5
H), 3.81 (d, J ¼ 4.9 Hz, 6H), 2.88 (dd, J ¼ 15.1, 5.3 Hz, 1H), 2.78 (d, J ¼ 15.2 Hz,
1
3
H). C NMR (100 MHz, CDCl ) d 168.6, 158.6, 158.0, 156.3, 147.0, 137.9, 135.8, 134.6,
3
28.8, 127.7, 127.4, 125.7, 125.6, 116.0, 113.9, 113.5, 112.9, 98.1, 57.5, 55.3, 55.2, 54.5,
1.0, 33.7. Anal. Calcd for C H N O : C, 76.13; H, 6.20; N, 5.38%. Found: C, 76.04;
3
3
32 2 4
þ
H, 6.26; N, 5.33%. MS (ESI) (m/z):521 [M þ H] .
Conclusions
In conclusion, we have developed an efficient and environmentally benign protocol for
the construction of highly functionalized tetrahydropyridine using catalytic amount of
VitB via one-pot multicomponent reaction of b-ketoester, substituted aldehydes, and
1
anilines. VitB is cheaply available and eco-benign. Good yield, usage of readily available
1
starting materials, operational simplicity, easy work-up procedures and eco-friendly
catalyst are the key features of this MCR protocol.
1
13
Full experimental details, H and
C NMR spectra can be found via the
“Supplementary content” section of this article’s webpage.
Acknowledgments
The authors are thankful to Department of Chemistry, University of Jammu for providing all
necessary facilities.

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Funding
The authors are thankful to University Grant Commission, New Delhi for Junior research fellow-
ship (S.S), Department of Science and Technology, Government of India, New Delhi for
INSPIRE fellowship (A.G) and NMR facility under PURSE.
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