One-pot five-component synthesis of highly functionalized piperidines using oxalic acid dihydrate as a homogenous catalyst

Article abstract of DOI:10.1016/j.cclet.2012.03.008

An efficient green protocol is described for the preparation of highly functionalized piperidines via a one-pot five-component reaction between aromatic aldehydes, anilines and β-ketoesters in the presence of oxalic acid dihydrate as catalyst in ethanol at ambient temperature. The structure as well as the relative stereochemistry of these compounds was confirmed by single X-ray crystallographic analysis.

Full text of DOI:10.1016/j.cclet.2012.03.008

Available online at www.sciencedirect.com
Chinese Chemical Letters 23 (2012) 569–572
www.elsevier.com/locate/cclet
One-pot five-component synthesis of highly functionalized
piperidines using oxalic acid dihydrate as a homogenous catalyst
a
Seyed Sajad Sajadikhah a, Malek Taher Maghsoodlou a, , Nourallah Hazeri ,
*
Sayyed Mostafa Habibi-Khorassani a, Anthony C. Willis b
a Department of Chemistry, The University of Sistan and Baluchestan, P.O. Box 98135-674, Zahedan, Iran
b Research School of Chemistry, The Australian National University, Canberra, ACT 0200, Australia
Received 26 December 2011
Available online 20 April 2012
Abstract
An efficient green protocol is described for the preparation of highly functionalized piperidines via a one-pot five-component
reaction between aromatic aldehydes, anilines and b-ketoesters in the presence of oxalic acid dihydrate as catalyst in ethanol at
ambient temperature. The structure as well as the relative stereochemistry of these compounds was confirmed by single X-ray
crystallographic analysis.
# 2012 Malek Taher Maghsoodlou. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Piperidine; Heterocycle; Homogeneous catalyst; Oxalic acid dihydrate; Multi-component reaction
Piperidines and their analogues are important core structures in many biologically active natural products [1].
These compounds exhibit diverse biological activities such as antimalarial [2], anti-hypertensive [3], antibacterial [4],
anticonvulsant and anti-inflammatory [5] a1-AB antagonists [6], therapeutic agents in the treatment of influenza
infection [7], cancer metastasis [8], diabetes [9], and also play important roles in many processes of disease treatments
[10,11]. Recently, the synthesis of highly functionalized piperidines have been reported using multi-component
reactions in the presence of L-proline/TFA [2], InCl3 [12], bromodimethylsulfonium bromide (BDMS) [13],
tetrabutylammonium tribromide (TBATB) [14], iodine [15], cerium ammonium nitrate (CAN) [16], ZrOCl2ꢀ8H2O
[17], picric acid [18], and silica-supported boron trifluoride (BF3ꢀSiO2) [19] as catalyst. Owing to the importance of
piperidines from a pharmaceutical and biological point of view, there is still the need to develop an efficient, mild and
environmentally benign protocol for the synthesis of highly substituted piperidines.
On the contrary, the use of organic catalysts has received considerable attention in organic synthesis due to their
important advantages, such as the possibility of performing reactions in the presence of acid-sensitive substrates,
performing reactions in milder reaction conditions, and selectivity [20].
As a part of our current studies on the development of efficient multi-component reactions for the preparation of
interesting bioactive molecules [21–24], especially piperidine synthesis [25], herein we present a simple and efficient
methodfor synthesisofhighlysubstituted piperidinesvia a one-potfive-componentreactionbetweenaromaticaldehydes,
anilines and b-ketoesters in the presence of oxalic acid dihydrate in ethanol at ambient temperature (Scheme 1).
* Corresponding author.
E-mail address: mt_maghsoodlou@yahoo.com (M.T. Maghsoodlou).
1001-8417/$ – see front matter # 2012 Malek Taher Maghsoodlou. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2012.03.008

570
S.S. Sajadikhah et al. / Chinese Chemical Letters 23 (2012) 569–572
R2
CHO
NH
O
2
R1
O
O
OR3
R1
4
3
Oxalic acid dihydrate
EtOH, rt
5
6
+
OR3
1
2
1
3
N
NH2
R1
2
R2
2
R2
4
Scheme 1. Synthesis of highly substituted piperidines 4.
In the initial experiment, the one-pot five-component reaction of 4-methyl benzaldehyde, aniline and ethyl acetoacetate
was chosen as the model reaction to optimize the reaction conditions. It is noteworthy that no product was obtained in the
absence ofcatalysteven after24 h,which indicated thatthecatalyst’s presenceis necessary for this transformation. Also, the
effect of different solvents and the effect of the amount of catalyst on the yield and rate of reaction were investigated. The
best result was achieved in the presence of 0.09 g of catalyst in ethanol at ambient temperature. Under the optimized
conditions, several reactions between different aromatic aldehydes, anilines, and methyl and/or ethyl acetoacetate were
examined. The results are summarized in Table 1. The substituents on the benzenering such as OMe, Me, F, Cl and Br were
tolerated during the reaction. In all cases, the one-pot five-component reaction proceeded smoothly to afford the
corresponding highly functionalized piperidines in good yields. The structures of compounds were deduced on the basis of
IR, 1H and 13C NMR spectroscopy, mass spectrometry, and elemental analysis. Also, the structure as well as the relative
stereochemistry of piperidine 4, for example, 4r, was further confirmed by single X-ray crystallographic analysis (Fig. 1).
On the basis of the proposed mechanism in the literature [14–16,25], it is reasonable to assume that piperidine 4
results in initial condensation of aromatic aldehyde and b-ketoester 3 with aniline in the presence of oxalic acid
dihydrate to give enamine 5 and imine 6. Then, enamine 5 reacts with imine 6 to produce intermediate 7 through
intermolecular Mannich-type reaction. The reaction between intermediate 7 and aldehyde gives intermediate 8. Next,
tautomerization of 8 generates intermediate 9, which immediately undergoes intramolecular Mannich-type reaction to
give intermediate 10. Eventually, the intermediate 10 tautomerizes to generate the desired piperidine derivative 4 due
to conjugation with the ester group (Scheme 2).
In conclusion, we have synthesized highly substituted piperidines via a one-pot five-component reaction between
aromatic aldehydes, anilines and b-ketesters in ethanol using oxalic acid dihydrate as a catalyst at ambient
Table 1
Synthesis of highly substituted piperidines 4.
Entry
R1
R2
R3
Product
Time (h)
Yield (%)a
mp (8C)
Lit. mp (8C)Ref,b
1
4-Me
4-Me
4-F
H
Et
4a
4b
4c
4d
4e
4f
12
12
10
12
10
16
12
12
10
12
12
16
12
12
15
12
11
12
12
84
81
84
78
80
67
78
85
83
82
73
77
81
85
80
84
85
84
82
227–230
214–216
202–204
218–220
185–186
178–181
190–192
219–221
217–219
190–192
159–161
193–195
228–231
204–205
173–175
200–202
185–186
169–171
196–198
228–231 [15]
215–217 [15]
205 [2]
2
H
Me
Me
Me
Me
Me
Me
Me
Me
Et
3
H
4
3-Cl
4-Cl
4-OMe
H
H
220 [2]
5
H
189–191 [13]
180 [2]
6
H
7
H
4g
4h
4i
194 [2]
8
H
4-Me
4-Me
4-Cl
4-Cl
4-Cl
4-Br
4-Me
4-Cl
4-Me
4-F
4-Me
4-Br
220–222 [17]
213–215 [17]
190 [2]
9
4-Cl
3-Cl
4-Br
4-OMe
4-Me
4-Me
4-F
10
11
12
13
14
15
16
17
18
19
4j
Me
Me
Me
Me
Me
Me
Et
4k
4l
160–163 [2]
195 [2]
4m
4n
4o
4p
4q
4r
4s
230–232 [15]
206–208 [15]
176 [2]
4-F
200–202 [25]
183–185 [25]
–
4-Me
4-Me
H
Et
Et
–
a
Isolated yield.
b
All knownproductshave been reportedpreviouslyin the literature and were characterizedby comparison ofIR and NMRspectrawithauthenticsamples.

S.S. Sajadikhah et al. / Chinese Chemical Letters 23 (2012) 569–572
571
Fig. 1. ORTEP representation of the X-ray structure of piperidine 4r.
R2
R1
R2
R2
NH
O
N
O
N
N
O
3
1
Oxalic acid
dihydrate
inter-molecular
OR3
OR3
R1
OR3
R1
Mannich reaction
1
2
5
HN
R1
N
R2
6
R2
R2
7
8
R2
R2
H
N
N
O
N
N
O
OR3
OR3
Oxalic acid
dihydrate
Oxalic acid
dihydrate
intra-molecular
Mannich reaction
4
R1
R1
R1
R1
R2
R2
9
10
Scheme 2. Proposed reaction mechanism for synthesis of highly substituted piperidines 4.
temperature. The present procedure offered several advantages such as mild and green reaction conditions, simplicity
in operation, inexpensive catalyst, and good to high yields, which makes it a useful and attractive process for synthesis
of these important compounds.
1 General procedure for synthesis of highly substituted piperidine 4
Initially, a solution of aromatic amine (2 mmol) and b-ketoester (1 mmol) in ethanol (5 mL) was stirred for 30 min in
the presence of oxalic acid dihydrate (0.09 g) at ambient temperature. Then, the aromatic aldehyde (2 mmol) was added
and the reaction mixturewas allowed to stir for appropriate time (Table 1). The progress of the reaction was monitored by
TLC. Aftercompletion ofthe reaction, thetickprecipitatewas filtered off andwashed with ethanol(3 ꢁ 2 mL) togivethe
pure product. Physical and chemical data of unknown products are presented below.!
1.1 Ethyl 4-(p-tolylamino)-1,2,5,6-tetrahydro-1,2,6-trip-tolylpyridine-3-carboxylate (4r)
White solid; mp 169–171 8C; IR (KBr) (ymax/cmꢂ1): 3256 (NH), 1656 (C O); 1H NMR (400 MHz, CDCl3): d 1.49
(t, 3H, J = 7.0 Hz, OCH2CH3), 2.20 (s, 3H, CH3), 2.31 (s, 3H, CH3), 2.36 (s, 3H, CH3), 2.38 (s, 3H, CH3), 2.78 (dd, 1H,

572
S.S. Sajadikhah et al. / Chinese Chemical Letters 23 (2012) 569–572
J = 15.1, 2.4 Hz, H0-5), 2.87 (dd, 1H, J = 15.1, 5.6 Hz, H00-5), 4.37 (dq, 1H, J = 10.4, 7.2 Hz, OCHaHb), 4.48 (dq, 1H,
J = 10.4, 6.8 Hz, OCHaHb), 5.13 (d, 1H, J = 3.6 Hz, H-6), 6.23 (d, 2H, J = 8.4 Hz, ArH), 6.42 (s, 1H, H-2), 6.49 (d, 2H,
J = 8.8 Hz, ArH), 6.89 (d, 2H, J = 10.8 Hz, ArH), 6.93 (d, 2H, J = 7.6 Hz, ArH), 7.08–7.29 (m, 8H, ArH), 10.26 (s, 1H,
NH); 13C NMR (100 MHz, CDCl3): d 14.8 (OCH2CH3), 20.1 (CH3), 20.9 (CH3), 21.0 (CH3), 21.1 (CH3), 33.6 (C-5),
55.0 (C-2), 57.9 (C-6), 59.5 (OCH2CH3), 97.8 (C-3), 112.8, 124.8, 125.9, 126.4, 126.6, 128.9, 129.2, 129.3, 129.4, 135.4,
135.6, 136.4,140.0, 141.4,145.0,156.4(C-4), 168.3(C O);MS(EI, 70 eV)m/z(%):530(M+, 11), 457(3), 439(24), 320
(32), 208 (68), 115 (34), 91 (100), 77 (15), 55 (23%); anal. calcd. for C36H38N2O2: C 81.47; H 7.22, N, 5.28; found: C
81.61, H 7.29, N 5.35. Crystallographic data (excluding structure factors) for the structure in this paper have been
deposited with the Cambridge Crystallographic Data Centre as supplementary publication CCDC 851584 for 4r.
Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
(fax: +44-(0)1223-336033 or e-mail: deposit@ccdc.cam.ac.uk), or via www.ccdc.cam.ac.uk/data request/cif.
1..2 Ethyl 4-(4-bromophenylamino)-1-(4-bromophenyl)-1,2,5,6-tetrahydro-2,6-diphenylpyridine-3-carboxylate (4s)
White solid; mp 196–198 8C; IR (KBr) (ymax/cmꢂ1): 3248 (NH), 1648 (C O); 1H NMR (400 MHz, CDCl3): d 1.50
(t, 3H, J = 6.8 Hz, OCH2CH3), 2.74 (d, 1H, J = 15.2 Hz, H0-5), 2. 89 (dd 1H, J = 15.2, 5.6 Hz, H00-5), 4.35–4.40 (m,
1H, OCHaHb), 4.46–4.52 (m, 1H, OCHaHb), 5.13 (d, 1H, J = 4.0 Hz, H-6), 6.14 (d, 2H, J = 8.0 Hz, ArH), 6.41 (s, 1H,
H-2), 6.42 (d, 2H, J = 8.0 Hz, ArH), 7.14–7.34 (m, 14H, ArH), 10.26 (s, 1H, NH); 13C NMR (100 MHz, CDCl3): d 14.8
(OCH2CH3), 33.4 (C-5), 55.2 (C-2), 58.3 (C-6), 59.9 (OCH2CH3), 98.8 (C-3), 108.4, 114.6, 119.1, 126.3, 126.5, 126.6,
127.2, 127.5, 128.4, 128.8, 131.6, 132.0, 136.9, 142.1, 143.2, 145.9, 155.2 (C-4), 168.1 (C O); MS (EI, 70 eV) m/z
(%): 634 (M + 2, 5), 632 (M+, 3), 555 (19), 447 (100), 324 (58), 296 (26), 278 (28), 252 (44), 115 (40), 91 (51), 77 (33),
55 (66); anal. calcd. for C32H28Br2N2O2: C 60.78; H 4.46, N, 4.43; found: C 61.04, H 4.57, N 4.47.
Acknowledgments
We gratefully acknowledge financial support from the Research Council of the University of Sistan and
Baluchestan and the Australian National University.
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