Metal-free, one-pot, rapid synthesis of tetrahydropyridines using acetic acid as solvent and catalyst at room temperature

Article abstract of DOI:10.1080/00397911.2013.838266

Acetic acid-promoted, one-pot synthesis of tetrahydropyridines has been developed under metal-catalyst-free conditions via a tandem reaction. High atom economy, good yield, simple procedure, no expensive column chromatography, shorter reaction time, and metal-free and mild reaction conditions are some of the important features of this protocol. The current methodology provides an alternative approach for not only highly substituted tetrahydropyridines (THPs) but also fully substituted tetrahydropyridines (FTHPs) in moderate to good yields. The plausible mechanism for the formation of THPs was greatly promoted by the H⁺ ion coming from acetic acid. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications for the following free supplemental resource(s): Full experimental and spectral details.]

Full text of DOI:10.1080/00397911.2013.838266

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Metal-Free, One-Pot, Rapid Synthesis
of Tetrahydropyridines Using Acetic
Acid as Solvent and Catalyst at Room
Temperature
Umamahesh Balijapalli a , Sathishkumar Munusamy a , Karthikeyan
Natesan Sundaramoorthy b & Sathiyanarayanan Kulathu Iyer a
a Chemistry Division, School of Advanced Sciences , Vellore Institute
of Technology , Vellore , India
b Science and Humanities, Department of Chemistry , Vel Tech Multi
Tech Dr. Rangarajan Dr. Sakunthala Engineering College , Chennai ,
India
Published online: 24 Feb 2014.
To cite this article: Umamahesh Balijapalli , Sathishkumar Munusamy , Karthikeyan Natesan
Sundaramoorthy & Sathiyanarayanan Kulathu Iyer (2014) Metal-Free, One-Pot, Rapid Synthesis of
Tetrahydropyridines Using Acetic Acid as Solvent and Catalyst at Room Temperature, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
44:7, 943-953, DOI: 10.1080/00397911.2013.838266
To link to this article: http://dx.doi.org/10.1080/00397911.2013.838266
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Synthetic Communications1, 44: 943–953, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.838266
METAL-FREE, ONE-POT, RAPID SYNTHESIS
OF TETRAHYDROPYRIDINES USING ACETIC ACID AS
SOLVENT AND CATALYST AT ROOM TEMPERATURE
Umamahesh Balijapalli,1 Sathishkumar Munusamy,1
Karthikeyan Natesan Sundaramoorthy,2 and
Sathiyanarayanan Kulathu Iyer1
1Chemistry Division, School of Advanced Sciences, Vellore Institute
of Technology, Vellore, India
2Science and Humanities, Department of Chemistry, Vel Tech Multi Tech
Dr. Rangarajan Dr. Sakunthala Engineering College, Chennai, India
GRAPHICAL ABSTRACT
Abstract Acetic acid–promoted, one-pot synthesis of tetrahydropyridines has been
developed under metal-catalyst-free conditions via a tandem reaction. High atom economy,
good yield, simple procedure, no expensive column chromatography, shorter reaction time,
and metal-free and mild reaction conditions are some of the important features of this
protocol. The current methodology provides an alternative approach for not only highly sub-
stituted tetrahydropyridines (THPs) but also fully substituted tetrahydropyridines
(FTHPs) in moderate to good yields. The plausible mechanism for the formation of THPs
was greatly promoted by the Hþ ion coming from acetic acid.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications1 for the following free supplemental resource(s):
Full experimental and spectral details.]
Keywords Acetic acid; acetoacetic esters; diastereoselectivity; intramolecular Mannich
cyclization; tandem reaction; tetrahydropyridines
Received February 26, 2013.
Address correspondence to Sathiyanarayanan Kulathu Iyer, Chemistry Division, School of
Advanced Sciences, Vellore Institute of Technology, Vellore 632014, India. E-mail: sathiya_kuna@
hotmail.com
943

944
U. BALIJAPALLI ET AL.
INTRODUCTION
Multicomponent reactions (MCRs) have received considerable attention
because of the complexity of the molecules that can be easily achieved from readily
available starting materials in one reaction sequence.[1] MCRs generally occur in one
pot and exhibit high atom economy and product selectivity. In most of the cases,
they yield a single product and thus MCRs are advantageous over linear stepwise
synthesis because of operational simplicity, reduction in reaction time, ecological
friendliness, saving of money and raw materials, inexpensive purification, and
avoidance of protection and deprotection processes.[2] Green chemistry involves
optimization of synthetic methodology without polluting the environment and
reducing the cost. In this regard we have focused our attention on the synthesis of
tetrahydropyridines at room temperature without using metal catalyst.
Tetrahydropyridines are widely distributed in naturally occurring alkaloids
and synthetic drugs.[3] A variety of structural features are exhibited by synthetically
prepared piperidines, including many exhibit significant biological properties. Many
synthetic methods have been extensively studied for tetrahydropyridines because of
their antihistamic,[4] anti-HIV,[5] anticancer,[6] antimicrobial,[7] antimalarial,[8]
anti-inflammatory,[9] and anti-insecticidal activity.[10] A few of them are also potent
inhibitors for many biological systems.[11] Considerable effort has been focused on
synthetic methods and some of the synthetic routes have been recommended for
the synthesis of highly substituted tetrahydropyridines.[12] Recently one-pot
syntheses of these scaffolds have been achieved by employing InCl3,[13] bromodi-
methylsulfonium bromide,[14] L-proline trifluoroacetic acid=TFA,[8] tetrabutyl
ammonium tribromide,[15] molecular I2,[16] ceric ammonium nitrate (CAN),[17]
ZrOCl 8H O,[18] picric acid,[19] BF3-SiO2[20], VCl3,[21] thiourea dioxide (TUD),[22]
2ꢀ
2
Bi(NO ) 5H O,[23] and LaCl 7H O[24] as efficient catalysts. These methods have
3 3ꢀ
3ꢀ
2
2
some disadvantages, such as the use of expensive and excess amounts of catalysts.
Therefore, the development of a simple, nontoxic, and effective synthetic strategy
is needed for the synthesis of biologically active molecules.
Glacial acetic acid is an excellent polar protic solvent, and the hydrogen in the
carboxylic group of acetic acid can easily be separated from the molecule by ioniza-
tion, which gives an environment for the reaction to proceed faster. Na et al.
developed a brand-new, bowl-shaped molecular architecture from the reaction of
ninhydrin and phloroglucinol in acetic acid in excellent yields up to 95% via
Scheme 1. Metal-free synthesis of highly substituted tetrahydropyridines using acetic acid. (Figure is
provided in color online.)

METAL-FREE SYNTHESIS OF TETRAHYDROPYRIDINES
945
MCR.[25] In the present report, we have explored acetic acid–promoted efficient
synthesis and mechanistic investigations of the formation of THPs using an MCR
(Scheme 1). Furthermore, the reaction is metal free; acetic acid is cheap, readily
available, versatile, and efficient for promotion of many acid-catalyzed organic
reactions.[26]
RESULTS AND DISCUSSION
Initially, the reaction of ethyl acetoacetate (EAA) (1 mmol), benzaldehyde
(2 mmol), and aniline (2 mmol) in ethanol was examined in the presence of a catalytic
amount of various Lewis acids (AlCl3, FeCl3, LaCl3, ZnCl2, NiCl2, and CuCl2), and
other catalysts (SiO2Cl, Al2O3, La2O3, triethyl amine, and Li2CO3 þ L-proline) (SI
Table 1). Interestingly, we ended up with THP 5a in up to 80% yield in 4–16 h (SI
Table1). When methanol was used as solvent, the catalysts LaCl3 and SiO2Cl offered
THP 5a in 80% and 78% yields, respectively. For the optimization and identification
of the suitable solvent and effective reaction conditions, EAA, benzaldehyde, aniline,
and 10 mol% of catalyst were selected as prototypes. Among the chosen solvents,
MeOH was considered the best for the synthesis of tetrahydropyridines. Although
acetonitrile, chloroform, ethanol, and dichloromethane allowed the reaction at a
Table 1. Screening of various solvents for the one-pot synthesis of tetrahydropyridine 5aa
Entry
Catalyst
Solvent
MeOH
EtOH
Time (h)
Yield (%)b
1
2
None
None
None
None
None
None
None
None
None
None
None
None
None
48
48
48
48
48
48
48
48
48
40
48
48
0.5
20
15
5
3
i-PrOH
n-BuOH
CH3CN
DCM
4
1
5
13
0
6
7
THF
0
8
Ethylacetate
Acetone
Toluene
Water
2
9
0
10
11
12
13
0
0
HCOOH
AcOH
0
94
aConditions: Ethyl acetoacetate (0.5 mmol), benzaldehyde (1 mmol), and aniline (1 mmol)
in solvent (3 ml), with stirring in room temperature.
bIsolated yields.

946
U. BALIJAPALLI ET AL.
faster rate, the yield was less than the yield obtained using MeOH as solvent. THF
and ethyl acetate gave poor yields, and no desired product was obtained with water.
Interestingly, when we performed the reaction with acetic acid as solvent, we
obtained 93% yield of the desired product THP 5a within 30 min.
To examine the role of the catalyst, we performed the same reaction with dif-
ferent catalysts in acetic acid. We employed 10 mol% catalyst for the model reaction
in acetic acid at room temperature but there was no significant change in the reaction
time and yield. Then, it was of interest to know whether it was possible to synthesize
a substituted tetrahydropyridine by this MCR in the absence of a catalyst. For this,
aniline was treated with 1 equivalent of EAA in the solvent to form enamine in situ
at room temperature. Similarly, 2 equivalents of aryl aldehyde and 1 equivalent of
aniline were mixed separately in the solvent to form Schiff’s base. Then these two
were stirred along with 1 mol of benzaldehyde (benzaldehyde was added in excess
during the formation of Schiff’s base) for up to 48 h.
To study the effect of the solvent on the reaction, the reaction was carried out
with various aprotic and protic solvents as shown in Table 1. In conclusion, we
found that proton is not catalyzing the reaction but acetic acid is the specific catalyst.
We got the desired THP in excellent yields with reaction time of 20 min using acetic
acid as solvent at room temperature. There were no other side products, and predo-
minantly antiselectivity was achieved. According to our knowledge there are only a
few reports available in the literature for the synthesis of THPs that require less than
5h under reflux condition with moderate yields.[18] In the present protocol, we
obtained excellent yields up to 96% and lowered the reaction time to 20 min without
reflux conditions. As far as the temperatute effect is concerned, it does not have any
significant effect on yield and the reaction time, because we are getting same yield
at the same interval of time at all temperatures.
To further explore the scope and importance of this five-component reaction
under optimized conditions,
a variety of aromatic aldehydes containing
electron-donating and electron-withdrawing substituents in the aromatic ring such
as -F, -Cl, -Br, -NO2, -CN, -Me, -OMe, and -Et were reacted with varying b-keto
esters and a number of substituted amines. The reaction time and percentage yield
for each of the product are shown in Table 2. To analyze the ester group effect on
the yields of THPs, a mixture of benzaldehyde and p-chloroaniline was treated sep-
arately with methyl acetoacetate (MAA), ethyl acetoacetate (EAA), allyl acetoacetate
(AAA), and benzyl acetoacetate (BAA) under the standard conditions. They yielded
the corresponding THP scaffolds in 84%, 89%, 83%, and 80% yields, respectively
(Table 2, entries 9, 22, 32, and 36). To study the substituent effect on aniline, a variety
of anilines possessing electron-donating and electron-withdrawing substituents in the
aromatic ring such as -Cl, -NO2, and -Me were treated with a variety of aromatic
aldehydes and EAA, and the results are summarized in Table 2 (entries 22–28).
Generally, for incorporating substitution at all the positions of the tetrahydro-
pyridine ring, ethyl butyryl acetate (EBA), aniline, and substituted aryl aldehydes
were allowed to react in acetic acid medium and we got fully substituted tetrahydro-
pyridines (FTHPs) with good yields up to 89%, 87%, and 87% for 6a, 6b, and 6c
respectively (Table 2, entries 29, 30, and 31). In the next attempt, for generating
tetrahydropyridine moiety with alkyl substitution at 2 and 6 positions, we treated
EAA and aniline with different aliphatic aldehydes including formaldehyde,

METAL-FREE SYNTHESIS OF TETRAHYDROPYRIDINES
947
Table 2. Three-component, one-pot reaction leading to substituted tetrahydropyridines under acetic acid
conditionsa
Entry
R1
R2
R3
Me
R4
Product (4–9)
Time (min)
Yield (%)b
1
2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Et
Et
Et
H
H
H
H
H
4a
4b
4c
4d
4e
4f
27
45
50
35
35
47
30
25
32
60
30
25
42
40
44
55
50
25
33
35
39
45
30
40
20
30
20
60
120
90
75
50
55
45
60
75
90
86
76
94
95
78
96
89
84
86
92
93
81
86
84
71
86
94
90
96
94
89
91
86
94
91
95
79
89
87
87
83
70
88
84
80
2-OMe
3-NO2
4-CN
4-Br
4-NO2
4-Me
4-MeO
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
3
4
5
6
7
4g
4h
4i
8
9
4-Cl
4-Cl
4-Cl
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
4-F
4j
4-Me
H
2-F
4k
5a
5b
5c
5d
5e
5f
H
Et
Et
3-F
H
3-Br
3-NO2
3-Me
4-Me
4-Et
4-F
H
Et
Et
H
H
Et
Et
H
5g
5h
5i
H
Et
Et
H
4-Cl
H
H
Et
Et
5j
4-Cl
4-Cl
4-Cl
4-Me
4-Me
4-Me
4-NO2
H
5k
5l
4-Me
4-Et
H
Et
Et
5m
5n
5o
5p
5q
6a
6b
6c
7a
7b
7c
8a
8b
Et
Et
4-Me
4-Cl
4-Me
4-F
Et
Et
Et
Et
4-Cl
4-CN
H
H
H
Et
4-Cl
4-Cl
4-Cl
H
Allyl
Allyl
Allyl
Benzyl
Benzyl
3-NO2
4-Me
H
H
4-Cl
aConditions: 1,3-dicarbonyl compound (0.5 mmol), aromatic aldehyde (1 mmol), and aniline (1 mmol) in
2.5 ml of acetic acid with stirring at room temperature.
bIsolated yields.

948
U. BALIJAPALLI ET AL.
Figure 1. X-ray crystal structure (ORTEP diagrams) of 5p and 6b. (Figure is provided in color online.)
acetaldehyde, and propanaldehyde under the same reaction conditions. However, no
desired compounds were formed in the reaction mass with up to 48 h of stirring. This
is due to the difficulty in generating Schiff base from aliphatic aldehydes with aniline
because of the electron-releasing nature of alkyl groups in aliphatic aldehydes. The
dehydration from the aldol product is difficult and the in situ–formed product is
highly unstable.
All the synthesized products were characterized by Fourier transform infrared
1
(FTIR), H NMR, 13C NMR, and high-resolution mass spectral (HRMS) analyses.
The structures of 4a, 5a, 5p, and 6b were determined by single-crystal x-ray
diffraction analysis and it can be concluded that the ring exists in trans form. The
x-ray structures of 5p and 6b are shown in Fig. 1. The anticonformation was
Scheme 2. Synthesis of intermediate 9, which is similar to key intermediate 10. (Figure is provided in color
online.)

METAL-FREE SYNTHESIS OF TETRAHYDROPYRIDINES
949
confirmed by comparing the spectroscopic studies and the single-crystal x-ray dif-
fraction analysis of 4a, 5a, and 5p with the literature, and it was concluded that
the reaction was predominantly diastereoselective.
To find the exact mechanism of the reaction, we treated parent benzaldehyde
and aniline with EBA under similar conditions in the molar ratio of 1:1:1. We had
successfully isolated the intermediate 9, which is very similar to 10, and intermediate
10 could not be isolated. Because first aniline and ketone react, we do not get the
product if we add 1 mol of aniline to intermediate 9 (Scheme 2). Earlier workers
isolated a similar intermediate with diethylmalonate[16,20] and acetophenone[21] but
failed to isolate an intermediate possessing both ester and alkyl moiety.
Scheme 3. Possible mechanism for the formation of THPs. (Figure is provided in color online.)

950
U. BALIJAPALLI ET AL.
To understand the most predominant mechanism for the formation of functio-
nalized tetrahydropyridines, the stepwise reaction was carried out. The plausible
mechanism is outlined in Scheme 3. Initially, the reaction of aniline and EAA was
carried out to give the b-enaminone (12 and 12A) which was confirmed by thin-layer
chromatography (TLC). Similarly, the reaction of benzaldehyde and aniline was car-
ried out to give the corresponding Schiff’s base 11. Further, this enamine 12 and
Schiff’s base 11 underwent intermolecular Mannich reaction in the presence of Hþ
to afford intermediate 10, which was confirmed by TLC. However, the intermediate
9, which is similar to 10, was successfully isolated from the reaction mass and con-
firmed by NMR studies. In the presence of Hþ, the reaction of aldehyde with the
intermediate 10 proceeded quickly to generate the intermediate 13 by the elimination
of a H2O molecule. The intermediate 13 underwent protonation to generate the
intermediate 14A, which is less reactive. Then 14A underwent tautomerization to
give more reactive intermediate 14B, which furthermore underwent intramolecular
cyclization to give functionalized piperidine derivatives 4A. Thereafter, the piperi-
dine derivative 4A tautomerizes under acidic condition to provide the desired
functionalized tetrahydropyridine derivatives.
In the next attempt, enamine 12 was added to formaldehyde and aniline, but
the reaction did not occur among them. This confirms that there was no formation
of Schiff’s base 11A from aliphatic aldehyde and aniline. The reaction was carried
out by sequential addition of reactants as follows: 1 equivalent of 1,3-dicarbonyl
compound and 2 equivalents of amine in acetic acid. This mixture was stirred for
5 min, followed by the addition of 2 equivalents of aldehyde, and the stirring contin-
ued for an appropriate time. The intermediate 10 was formed easily by intermolecu-
lar Mannich reaction of 11 and 12 in the presence of Hþ, and also the reaction
between 10 and remaining aldehyde in the reaction mass was significantly influenced
by Hþ to the elimination of H2O. Hence, we concluded that the THPs were
efficiently synthesized via the intermediate 10 in the presence of Hþ.
EXPERIMENTAL
All the solvents and chemicals were received commercially. Melting points were
determined by using a Guna melting-point apparatus and are uncorrected. FTIR
spectra were recorded using a Jasco-4100 spectrometer instrument. NMR spectra
were taken with a Bruker AV III spectrometer at 500 MHz (1H and 13C) and at
400 MHz (1H and 13C) using CDCl3 as the solvent with tetramethylsilane (TMS)
as internal standard. HRMS analysis was obtained on a Jeol GC Mate.
General Procedure for the Preparation of Methyl
1,2,5,6-Tetrahydro-1,2,6-triphenyl-4-(phenylamino)
Pyridine-3-carboxylate (4a)
A mixture of methyl acetoacetate (1 mmol), aniline (2 mmol), and 3 ml glacial
acetic acid was stirred at room temperature for 5 min followed by the addition of ben-
zaldehyde (2 mmol) and allowed to stir for an appropriate time (Table 1). Completion
of the reaction was monitored by thin-layer chromatography (TLC) using a 1:9 ratio

METAL-FREE SYNTHESIS OF TETRAHYDROPYRIDINES
951
of ethylacetate and hexane. The solid product formed in the reaction mixture was
filtered, washed with methanol, and recrystallized using ethanol and THF (1:1 ratio).
Selected Data
White yellow solid; Melting point: 192–194 ꢁC: IR (KBr): 3250, 3024, 2949,
2867, 1815, 1661, 1606, 1504, 1449, 1375, 1321, 1245, 1183, 1070, 978, 920, 748,
1
646 cmꢂ1: H NMR (400 MHz, CDCl3) ppm: 2.78–2.74 (dd, J ¼ 32.0, 4 Hz, 1H),
2.89–2.84 (dd, J ¼ 32.0, 4.0 Hz, 1H), 3.93 (s, 3H), 5.14 (s, 1H), 6.28–6.26 (d,
J ¼ 8.0 Hz, 2H), 6.45 (s, 1H), 6.53–6.51 (d, J ¼ 8.0 Hz, 2H), 6.61–6.57 (t, J ¼ 8.0 Hz,
Hz, 1H), 7.33–7.03 (m, 15H), 10.25 (br s, 1H, NH); 13C NMR (100 MHz, CDCl3)
ppm: 33.6, 51.0, 55.1, 58.2, 97.9, 112.9, 116.2, 125.8, 125.9, 126.4, 126.4, 126.6,
127.2, 128.3, 128.7, 128.9, 128.9, 137.8, 142.7, 143.9, 146.9, 156.3, 168.6.
CONCLUSION
In conclusion, an efficient, simple, and acetic acid–promoted protocol for the
synthesis of highly functionalized tetrahydropyridines (THPs) by one-pot multicom-
ponent reaction is developed using readily available starting materials under
metal-free conditions. The advantageous features of this procedure are mild reaction
conditions, high diastereoseletivity, high atom economy, good yields, operational
simplicity, no tedious separation procedures, inexpensive starting materials,
metal-free synthesis, environmentally benign reaction, and short reaction times when
compared to the reaction catalyzed by the catalyst. The intermediate 9, which was
similar to the key intermediate for the formation of THP, was isolated by one-pot,
three-component reaction of EBA, aniline, and aldehyde. From the mechanistic
studies it is clearly known that the formation of THPs via intramolecular Mannich
reaction was influenced by Hþ.
SUPPLEMENTARY MATERIAL
1
General experimental details, characterization data of all the compounds, H
NMR and 13C NMR spectra of all the compounds, and crystallographic data of
4a, 5a, 5p, and 6b can be found online.
ACKNOWLEDGMENTS
B. U. M. and M. S. K. thank VIT management for providing financial support
through research associateships (RA). The authors express their gratitude to P. G.
Aravindan, SAS, VIT, Vellore, and G. Sekar, IIT, Madras, India, for crystal data.
B. U. M. thanks CSIR for providing SRF.
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