LaCl3·7H2O as an efficient catalyst for one-pot synthesis of highly functionalized piperidines via multi-component organic reactions

Article abstract of DOI:10.1007/s10562-012-0829-x

The three-component one-pot synthesis of highly functionalized piperidine derivatives was carried out by condensing 1,3-dicarbonyl compounds with aromatic aldehydes and aniline using a catalytic amount (10 mol%) of LaCl ₃·7H₂O in methanol at room temperature. The main features of current protocol include easy work up, mild reaction conditions, good yields and high atom economy. Springer Science+Business Media, LLC 2012.

Full text of DOI:10.1007/s10562-012-0829-x

Catal Lett (2012) 142:895–900
DOI 10.1007/s10562-012-0829-x
LaCl3Á7H2O as an Efficient Catalyst for One-Pot Synthesis
of Highly Functionalized Piperidines via Multi-component
Organic Reactions
•
Balijapalli Umamahesh Venkatesan Sathesh
•
•
•
Gunasekar Ramachandran Munusamy Sathishkumar
Kulatu Sathiyanarayanan
Received: 5 March 2012 / Accepted: 14 April 2012 / Published online: 15 May 2012
Ó Springer Science+Business Media, LLC 2012
Abstract The three-component one-pot synthesis of
highly functionalized piperidine derivatives was carried out
by condensing 1,3-dicarbonyl compounds with aromatic
aldehydes and aniline using a catalytic amount (10 mol%)
of LaCl3Á7H2O in methanol at room temperature. The main
features of current protocol include easy work up, mild
reaction conditions, good yields and high atom economy.
cleaved and twelve new bonds were constructed through
one-pot cascade reaction, while only two molecules of H2O
were removed. In most of the situations a single product
was obtained from three or more different, willingly
available starting materials in an illustrious synthetic
manner through MCRs [4]. The beneficial effects of these
MCRs over the conventional synthesis are shorter reaction
time, eco friendliness, cost effectiveness, high atom econ-
omy, inexpensive purification and no necessity for pro-
tection and deprotection process [5, 6]. Recently, Lewis
acids catalyzed Michael addition of Schiff base to enami-
nones has attracted great attention of synthetic chemists
[7, 8].
Keywords One-pot condensation Á Lanthanum chloride
heptahydrate Á Aza Diels–Alder reaction Á Knoevenagel
condensation Á Functionalized piperidines
1 Introduction
Poly functionalized piperidines are widely distributed in
naturally occurring monocyclic and bicyclic alkaloids and
synthetic drugs [9]. A variety of structural features sur-
rounded the naturally occurring and synthetically prepared
piperidines, among them many exhibit significant biologi-
cal properties including anti-HIV, anticancer, antimyco-
bacterial, antimicrobial, antimalarial, antiinflammatory,
antiinsecticidal and they are potent inhibitors for many
biological systems [10–14]. Much considerable efforts
have been focused on the synthetic methods and some of
the synthetic routes have been recommended for the syn-
thesis of highly substituted piperidines essentially intra-
molecular Mannich reaction [15], cyclohydrocarboxylation
[16], aziridine ring expansion [17], radical cyclization [18],
domino reaction [19], Diels–Alder reaction [20], imino
Diels–Alder reaction [21] and domino imino-aldol-aza-
Michael addition [22]. Recently one-pot synthesis of these
scaffolds has been achieved by employing InCl3 [23],
bromodimethylsulfonium bromide [24], L-proline/TFA
[25], tetrabutylammonium tribromide [26], molecular I2
[27], CAN [28], ZrOCl2Á8H2O [29], picric acid [30],
thiourea dioxide (TUD) [31], BF3-SiO2 [32], VCl3 [33] and
As an important aspect of synthetic organic chemistry,
multi-component organic reactions (MCRs) are among the
most prosperity reaction classes. 1,3-Dicarbonyl com-
pounds are one of the most multifaceted reagents to be used
in MCRs because of the high reactivity of enaminones in
both keto and enol forms, which are very advantageous to
construct useful bioactive heterocycles [1, 2]. MCRs offer
a highly valuable synthetic protocol for the construction of
highly complex molecules with minimum number of syn-
thetic steps. Wu et al. [3] has described the synthesis of
naphthyridine derivatives in which thirteen bonds were
Electronic supplementary material The online version of this
article (doi:10.1007/s10562-012-0829-x) contains supplementary
material, which is available to authorized users.
B. Umamahesh Á V. Sathesh Á G. Ramachandran Á
M. Sathishkumar Á K. Sathiyanarayanan (&)
Chemistry Division, School of Advanced Sciences,
VIT University, Vellore 632014, India
e-mail: sathiya_kuna@hotmail.com
123

896
B. Umamahesh et al.
Bi(NO3)3Á5H2O [34] as efficient catalysts. The above
deliberated methods have some disadvantages such as the
use of expensive and excess amount of catalysts. Effica-
cious new approaches for the preparation of chemically and
biologically active complex molecules are of great signif-
icance with simple mechanism and good selectivity.
Nowadays lanthanides including lanthanum [35], cerium
[36], samarium [37] and ytterbium [38] have been
employed as efficient catalysts for a wide variety of syn-
thetic reactions. Jun Lu et al. [39] has described an efficient
one-pot synthesis of 3,4-dihydropyrimidinones using lan-
thanum chloride heptahydrate as catalyst from an aldehyde,
b-keto ester and urea or thiourea in ethanol. In continuation
of this, here we report the one-pot efficient synthesis of
highly functionalized piperidines using 10 mol% of
LaCl3Á7H2O as a catalyst in a three-component intramo-
lecular aza Diels–Alder reaction.
acetate gave low yields and no desired product was
obtained with water.
By screening a wide range of catalysts, we found out
that the product 5a could be obtained in good yields
ranging from 20 to 83 % in different mole ratios of
LaCl3Á7H2O (1, 2, 5, 10 and 15 mol%) and the results are
summarized in Table 2. Better yields were obtained up to
83 % by carrying out the reaction using 10 mol% of
LaCl3Á7H2O in MeOH as solvent. The reaction takes place
efficiently in an open air system and it does not require any
special apparatus like Schlenk system. When the reaction
was carried out at reflux conditions, there was no signifi-
cant change in yields and time (Entry 16, Table 2). Primary
screening studies of a variety of catalysts also revealed that
lanthanum oxide and silica chloride also act as catalyst.
La2O3 (10 mol%) and silica chloride (10 mol%) were
employed as catalysts for the three-component reaction but
moderate yields were obtained. Lower yields were obtained
with the use of NH4OAc and ammonium molybdate.
A wide range of aromatic aldehydes and amines were
subjected to react with 1,3-dicarbonyl compounds in the
presence of catalytic amount of LaCl3Á7H2O and the results
are summarized in Table 3. A variety of aromatic alde-
hydes possessing electron withdrawing and electron
donating groups at different positions on the aromatic ring,
2 Result and Discussion
For the initial optimization of the reaction conditions and
the identification of the suitable solvent and effective
reaction conditions, ethyl acetoacetate, benzaldehyde, ani-
line and 10 mol% of catalyst was selected as prototype.
Among the chosen solvents MeOH was the best for the
synthesis of tetrahydropyridines showed in Table 1.
Although acetonitrile, chloroform and dichloromethane
allowed the reaction at a faster rate, the yield was less than
that obtained using MeOH as solvent. THF and ethyl
Table 2 Screening of catalysts for the one-pot synthesis of
tetrahydropyridines
Entry Catalyst (mol%)
Time (h) Yield (%)a
1
NH4OAc (10 mol%)
24
24
24
24
46
2
(NH4)6Mo7O24Á4H2O (10 mol%)
AlCl3 (10 mol%)
32
3
24
4
Triethyl amine (10 mol%)
Traces
40
Table 1 Initial solvent effect studies for synthesis of tetrahydro-
pyridines with 10 mol% catalyst
5
Li2O3 ? L-proline (10 ? 5 mol%) 24
6
Al2O3 acidic (10 mol%)
Al2O3 basic (10 mol%)
ZnCl2 (10 mol%)
24
24
24
24
18
3.5
3.5
3.5
3
35
Entry
Solvent
Catalyst
Time (h)
Yield (%)a
7
29
1
CH3CN
CH2Cl2
CHCl3
EtOAc
MeOH
EtOH
LaCl3Á7H2O
LaCl3Á7H2O
LaCl3Á7H2O
LaCl3Á7H2O
LaCl3Á7H2O
LaCl3Á7H2O
LaCl3Á7H2O
LaCl3Á7H2O
LaCl3Á7H2O
SiO2Cl
3
74
8
41
2
2.5
3
76
9
FeCl3 (10 mol%)
32
3
72
10
11
12
13
14
15
16
17
La2O3 (10 mol%)
65
4
10
3
44
SiO2Cl (10 mol%)
68
5
83
LaCl3Á7H2O (1 mol%)
LaCl3Á7H2O (2 mol%)
LaCl3Á7H2O (5 mol%)
LaCl3Á7H2O (10 mol%)
LaCl3Á7H2O (10 mol%)
LaCl3Á7H2O (15 mol%)
20
6
4
76
35
7
i-PrOH
THF
6.5
8
70
62
8
59
3
83
81b
9
H2O
12
3
Traces
71
3
10
11
12
MeOH
CH3CN
CHCl3
3
81
SiO2Cl
4.5
4
66
Conditions: ethyl acetoacetate (0.5 mmol), benzaldehyde (1 mmol),
aniline (1 mmol) and 10 mol% catalyst in methanol (5 ml), stirring in
room temperature
SiO2Cl
74
Conditions: ethyl acetoacetate (0.5 mmol), benzaldehyde (1 mmol),
aniline (1 mmol) and 10 mol% LaCl3Á7H2O in 5 ml solvent, stirring
in room temperature
a
Isolated yields
b
Isolated yield when the reaction was carried out under reflux
conditions
a
Isolated yields
123

LaCl3Á7H2O as an Efficient Catalyst
897
Likewise a variety of aromatic anilines possessing electron
withdrawing and electron donating groups, were allowed to
react with ethyl acetoacetate and aromatic aldehydes under
standard conditions and results are summarized in Table 3.
Similarly for getting piperidine moiety, we treated ethyl
acetoacetate and aniline with different aliphatic aldehydes
including formaldehyde, acetaldehyde, and propanalde-
hyde under same reaction conditions. However, no desired
compounds were formed in the reaction. This is due to the
electron releasing nature of alkyl groups in aliphatic
aldehydes. The reaction is shown in Scheme 1.
Table 3 LaCl3Á7H2O (10 mol%) catalyzed one-pot synthesis of
highly functionalized piperidines
Entry
R1
R2
R3
4, 5
Time (h)
Yield (%)a
1
H
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
4a
4b
4c
4d
4e
4f
3.5
3.5
5
80
68
70
78
81
62
88
84
84
52
79
83
69
73
70
49
66
69
67
77
82
80
73
69
80
82
77
74
2
2OMe
3NO2
4CN
4Br
4NO2
4Me
4MeO
H
H
3
H
4
H
4.5
5
5
H
6
H
4.5
3.5
4
7
H
4g
4h
4i
8
H
All the synthesized products were characterized by
FTIR, H1 NMR, C13 NMR and mass spectral analyses. The
structures of 4a and 5a were determined by single crystal
X-ray diffraction analysis shown in Fig. 1 and it can be
concluded that the ring exists in trans form. The H1 NMR
spectral analyses of compounds 4a–4j and 5a–5m reveal
that N–H peak comes around 10.250–10.350 ppm with the
exception of 4b which comes around 9.80 ppm. Proton
present at the stereogenic center C-2 (denoted by asterisk in
Scheme 2) position comes at around 6.35–6.55 ppm. Pro-
ton present at the stereogenic center is shifted towards the
deshielding region, when the electron donating groups are
present at para position on aromatic aldehyde ring. This is
further confirmed by H1 NMR spectra of compounds 5g–j.
In compound 5g and 5h stereogenic proton comes next to
two aromatic protons but in the case of 5i and 5j stereo-
genic proton comes first followed by aromatic proton.
The possible reaction mechanism for this three-compo-
nent reaction is described in Scheme 3. LaCl3Á7H2O is
Lewis acid, which serves as an acid catalyst for the con-
struction of b-enaminone (6) formed by the reaction of
ethyl acetoacetate with aniline and imine (7) which is
formed in the reaction of benzaldehyde with aniline (Step
1). Benzaldehyde which is retained in the reaction mixture
undergoes Knoevenagel condensation with b-enaminone
leading to the formation of intermediate 8 and reactive
form 8a (Step 2). Due to the diene core present in inter-
mediate 8a, it proceeds towards an intramolecular aza
Diels–Alder reaction with imine (serves as dienophile)
which affords the expected piperidine (Step 3). Interme-
diates 6 and 7 had earlier been isolated from similar
reaction.
9
4Cl
4Cl
4Cl
H
3.5
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
4F
4j
4Me
H
4k
5a
5b
5c
5d
5e
5f
3.5
3
2F
H
Et
7.5
3.5
5
3F
H
Et
3Br
3NO2
3Me
4Me
4Et
H
Et
H
Et
5.5
4.5
4
H
Et
H
Et
5g
5h
5i
H
Et
4.5
3.5
3.5
4
4F
H
Et
4Cl
H
H
Et
5j
4Cl
4Cl
4Cl
4Me
4Me
4Me
4NO2
Et
5k
5l
4Me
4Et
Et
3.5
4.5
4.5
4
Et
5m
5n
5o
5p
5q
H
Et
4Me
4Cl
4Me
Et
Et
5
Et
8
Conditions: 1,3-dicarbonyl compound (0.5 mmol), aromatic aldehyde
(1 mmol), aniline(1 mmol) and 10 mol% LaCl3Á7H2O in 5 ml
MeOH, stirring in room temperature
a
Isolated yields
were allowed to react with ethyl acetoacetate under stan-
dard conditions affording substituted piperidine with good
yields. Nitro group (at 3 and 4 positions) containing alde-
hyde gave moderate yields with both ethyl acetoacetate
and methyl acetoacetate due to stable imine formation.
Scheme 1 Reaction of 1,3-
dicarbonyl compound, aniline
with various aldehydes in the
presence of LaCl3Á7H2O
123

898
B. Umamahesh et al.
Fig. 1 Crystal structures of 4a
and 5a
Scheme 2 Three-component
one-pot reaction leading to poly
substituted piperidines
3 Experimental Section
room temperature for 15 min followed by the addition of
aldehyde (2 mmol) and stirring was continued for an
appropriate time. The completion of the reaction was
monitored by TLC. The solid product formed in reaction
mixture was filtered, washed with methanol and recrystal-
lized using ethanol and tetrahedrofuran (1:1 ratio). If the
product was in gel form, it was purified by silica gel column
chromatography using hexane and ethyl acetate as eluant.
3.1 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 b-keto ester (1 mmol), aniline (2 mmol) and
LaCl3Á7H2O (0.1 mmol) in 5 ml methanol was stirred at
123

LaCl3Á7H2O as an Efficient Catalyst
899
Scheme 3 The possible
mechanism for three-component
one-pot reaction leading to poly
substituted piperidine
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,
646 cm-1: H1NMR (400 MHz, CDCl3)TM ppm: 2.78–2.74
(d, J = 14.8 Hz, 1H), 2.89–2.84 (dd, J = 30.4, 5.6 Hz,
1H), 3.93 (s, 3H), 5.15(s, 1H), 6.29–6.26 (d, J = 7.6 Hz,
2H), 6.45 (s, 1H), 6.53–6.51 (d, J = 8.4 Hz, 2H),
6.61–6.58 (t, J = 7.2 Hz, 1H), 7.33–7.03 (m, 15H), 10.25
(br s, 1H, NH); C13NMR (100 MHz, CDCl3)TM 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;
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4 Conclusion
In conclusion, we have developed a one-pot three-com-
ponent intramolecular aza Diels–Alder reaction of alde-
hydes, aniline and 1,3-dicarbonyl compounds in the
presence of 10 mol% of LaCl3Á7H2O in MeOH as an
efficient catalyst. The main feature of this strategy includes
easy work up, mild reaction conditions, good yields and
high atom economy. The current methodology is attractive
for the preparation of a wide variety of biologically active
highly functionalized piperidines.
Acknowledgments Umamahesh B and Sathesh V express their
thanks to VIT management for providing financial support through
research associateship. The authors express their gratitude to Dr. T. N.
Guru Row, IISc, Bangalore and G. Sekar, IIT, Madras, India for
crystal data.
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