Fe(NO3)3·9H2O as efficient catalyst for one-pot synthesis of highly functionalized piperidines

Article abstract of DOI:10.1002/jccs.201200421

Fe(NO₃)₃·9H₂O is used as an efficient and effective catalyst for the one-pot three-component synthesis of highly functionalized piperidines from aromatic aldehydes, anilines and β-ketoesters in ethanol at ambient temperature. This procedure includes some important aspects like the easy work-up, no need to column chromatography, simple and readily available precursors, and good to high yields.

Full text of DOI:10.1002/jccs.201200421

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Article
Fe(NO3)3×9H2O as Efficient Catalyst for One-pot Synthesis of Highly Functionalized
Piperidines
Nourallah Hazeri,* Malek Taher Maghsoodlou, Sayyed Mostafa Habibi-Khorassani,
Jasem Aboonajmi and Seyed Sajad Sajadikhah
Department of Chemistry, University of Sistan and Baluchestan, P.O. Box 98135-674, Zahedan, Iran
(Received: Aug. 2, 2012; Accepted: Oct. 31, 2012; Published Online: Dec. 20, 2012; DOI: 10.1002/jccs.201200421)
Fe(NO3)3·9H2O is used as an efficient and effective catalyst for the one-pot three-component synthesis of
highly functionalized piperidines from aromatic aldehydes, anilines and b–ketoesters in ethanol at ambi-
ent temperature. This procedure includes some important aspects like the easy work-up, no need to col-
umn chromatography, simple and readily available precursors, and good to high yields.
Keywords: Heterocycle; Piperidine; Fe(NO3)3·9H2O; Multi-component reaction.
INTRODUCTION
The piperidine ring system is one of the most com-
presence of L-proline/TFA,10 InCl3,18,19 bromodimethyl-
sulfonium bromide (BDMS),20 tetrabutylammonium tri-
bromide (TBATB),21 iodine,22 cerium ammonium nitrate
(CAN),23 ZrOCl2·8H2O,24 BF3·SiO2,25 Bi(NO3)3·5H2O,26
picric acid,27 p-TsOH·H2O,28 AcOH,29 and oxalic acid di-
hydrate30 as catalyst. Owing to the importance of piperi-
dines from pharmaceutical and biological view, introduc-
tion of an efficient method for the preparation of these com-
pounds is still in demand. As part of our continuing interest
in the development of multi-component reactions,31-34
herein we report a one-pot three (is situ five)-component
synthesis of highly functionalized piperidine 4 from the re-
action of aromatic aldehyde 1, aromatic amine 2, and b-
ketoester 3 in the presence of Fe(NO3)3·9H2O (20 mol %)
in ethanol at ambient temperature (Scheme I).
mon motifs found in numerous drugs, drug candidates and
natural products such as alkaloides.1-3 compounds with this
ring exhibit anti-hypertensive,4 antibacterial,5 neuro-pro-
tective agents,6,7 anticonvulsant and anti-inflammatory
agents,8,9 and also antimalarial activities.10 Furthermore,
these are intricately involved in the MAO based mecha-
nism of Parkinson’s disease11 and as inhibitors of farnesyl
transferase12 and dihydroorate dehydrogenase13 and also
play key roles in many disease processes. Also substituted
piperidines have been identified as an important class of
therapeutic agents in the treatment of influenza infection,14
cancer metastatis,15 viral infections including AIDS,16 and
diabetes17 (Fig. 1).
As a result, various synthetic approaches have been
developed for the synthesis of these important compounds.
Recently, the synthesis of highly functionalized piperidines
have been reported using multi-component reactions in the
Synthesis of highly functionalized piperi-
Scheme I
dine 4
R2
CHO
OH
NH
4
O
2
2
O
O
OH
3
R1
OR3
Fe(NO3)3.9H2O
EtOH, rt
5
6
HN
N
1
OR3
2
+
N
3
F
N
NH2
1
R1
OH
O
R1
R2
neuro-protective agents6,7
2
R2
4
R
O
N
RESULTS AND DISCUSSION
NH
R: H, OH, OMe
Initially, the reaction of 4-methyl benzaldeyde, ani-
line and methyl acetoacetate was chosen as a model reac-
tion for the synthesis of corresponding highly substituted
piperidine 4a. Various potential catalysts were tested in dif-
anticonvulsant agent8
Fig. 1. Pharmaceutically active compounds containing
piperidine framework.
* Corresponding author. Tel: +98-541-2416586; Fax: +98-541-2416586; E-mail: n_hazeri@yahoo.com
J. Chin. Chem. Soc. 2013, 60, 355-358
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355

Article
Hazeri et al.
Table 1. The effect of different catalyst on the synthesis of
piperidine 4a[a]
ferent solvents at ambient temperature. As shown in Table
1, the best result was obtained in the presence of 20 mol%
Fe(NO3)3·9H2O in EtOH (Table 1, Entry 14). It is notewor-
thy that the increasing of catalyst loading to 25 mol% had
no improving effect on the yield of product. When the reac-
tion proceeded in the absence of catalyst no product was
obtained, which this observation indicated that the cata-
lyst’s presence is necessary for this transformation. Low
yields were obtained when water or solvent-free conditions
was employed.
Yield
(%)[b]
Entry
Catalyst (mol%)
Solvent Time (h)
1
LiCl (10)
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
MeOH
MeCN
H2O
48
48
48
48
48
48
24
48
24
24
12
18
6
¯
5
2
KI (10)
3
CuCl2 (10)
38
25
¯
¯
35
10
30
50
72
55
84
91
90
87
70
30
37
¯
4
Al2(SO4)3·18 H2O (10)
Cu(OAc)2·H2O (10)
AgNO3 (10)
5
6
7
Zr(NO3)2 (10)
8
Mg(NO3)2·4H2O (10)
Zn(NO3)2·6H2O (10)
Mn(NO3)2·4H2O (10)
Fe(NO3)3·9H2O (10)
Fe(NO3)3·9H2O (5)
Fe(NO3)3·9H2O (15)
Fe(NO3)3·9H2O (20)
Fe(NO3)3·9H2O (25)
Fe(NO3)3·9H2O (20)
Fe(NO3)3·9H2O (20)
Fe(NO3)3·9H2O (20)
Fe(NO3)3·9H2O (20)
No Catalyst
To investigate the generality and the scope of this
one-pot three-component reaction, the optimized reaction
conditions as described above was extended to various aro-
matic aldehyde, aromatic amine and methyl and/or ethyl
acetoacetate. The results are summarized in Table 2. Vari-
ous sensitive functionality groups such as Me, OMe, NO2,
F, Cl and Br were tolerated during the reaction. All reac-
tions proceeded efficiently and cleanly and the desired
products were obtained in good to excellent yields. How-
ever, no product was obtained from the reaction of p-di-
methylamino benzaldehyde, p-anisidine and methyl aceto-
acetate (Table 2, entry 29). The structures of all compounds
were characterized by comparison of IR, 1H and 13C NMR
spectra with authentic samples. Also, the relative stereo-
chemistry of these piperidines has been confirmed by sin-
gle X-ray crystallography analysis in previously reported
literature.18-26,30
9
10
11
12
13
14
15
16
17
18
18
20
5
5
5
7
24
16
48
Neat
EtOH
[a] Experimental conditions: 4-methyl benzaldehyde (2 mmol),
aniline (2 mmol), and methyl acetoacetate (1 mmol), rt. [b] Iso-
lated yield.
data of selected products are represented below.
Methyl 1-phenyl-4-(phenylamino)-2,6-dip-tolyl-1,2,5,6-
tetrahydropyridine-3-carboxylate (4a)
In summary, an efficient and simple method has been
developed for the formation of highly functionalizaed
piperidines via one-pot three-component reaction cata-
lyzed by Fe(NO3)3·9H2O. This methodology offered sev-
eral advantages such as mild reaction conditions, simplic-
ity in operation, good to excellent yields, simple and readily
available precursors, which make it a useful and attractive
process for synthesis of these important compounds.
1
White solid. H NMR (400 MHz, CDCl3): d 2.25 (3H, s,
CH3), 2.32 (3H, s, CH3), 2.75 (1H, dd, J = 15.2, 2.4 Hz, H¢-5),
2.84 (1H, dd, J = 15.2, 5.6 Hz, H²-5), 3.93 (3H, s, OCH3), 5.09
(1H, d, J = 3.1 Hz, H-6), 6.32 (2H, d, J = 8.0 Hz, ArH), 6.37 (1H,
s, H-2), 6.48 (2H, d, J = 8.8 Hz, ArH), 6.60 (1H, t, J = 7.2 Hz,
ArH), 7.00-7.12 (11H, m, ArH), 7.20 (2H, d, J = 8.0 Hz, ArH),
10.29 (1H, s, NH).
Ethyl 4-(3,4-dichlorophenylamino)-1-(3,4-dichloro-
phenyl)-2,6-dip-tolyl-1,2,5,6-tetrahydropyridine-3-car-
boxylate (4i)
EXPERIMENTAL
General procedure for synthesis of highly function-
alized piperidine 4
White solid. 1H NMR (400 MHz, CDCl3): d 1.50 (3H, t, J =
6.4 Hz, OCH2CH3), 2.34 (3H, s, CH3), 2.35 (3H, s, CH3), 2.73
(1H, d, J = 15.2 Hz, H¢-5), 2.90 (1H, dd, J = 15.2, 5.6 Hz, H²-5),
4.31-4.40 (1H, m, OCHaHb), 4.46-4.54 (1H, m, OCHaHb), 5.08
(1H, br s, H-6), 6.16 (2H, d, J = 7.2 Hz, ArH), 6.36 (1H, s, H-2),
6.43 (2H, d, J = 7.8 Hz, ArH), 6.96-7.23 (10H, m, ArH), 10.24 (s,
1H, NH); 13C NMR (100 MHz, CDCl3): d 14.8 (OCH2CH3), 21.6
(CH3), 21.8 (CH3), 33.4 (C-5), 55.3 (C-2), 58.2 (C-6), 59.8
(OCH2CH3), 98.9 (C-3), 108.3, 114.6, 119.2, 123.5, 123.5, 126.9,
First, a solution of aromatic amine (2 mmol) and b-keto-
ester (1 mmol) in ethanol (5 mL) was stirred for 30 min in the
presence of Fe(NO3)3·9H2O (20 mol%) at ambient temperature.
Next, the aromatic aldehyde (2 mmol) was added and the reaction
mixture was allowed to stir for appropriate time. The progress of
the reaction was monitored by TLC. After completion of the reac-
tion, the resulting precipitates were collected by filteration and
washed with EtOH (3 × 2 mL) to give the pure product. Spectral
356
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JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Synthesis of Highly Functionalized Piperidines
Table 2. The synthesis of highly substituted piperidine 4a-4ab
Entry
R1
R2
R3
Product
Time (h) Yield (%)[a]
m.p. (lit. reported)Ref.,[ b]
1
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-OMe
4-OMe
4-OMe
4-OMe
4-F
H
H
Me
Et
4a
4b
5
5
7
6
6
5
6
7
7
8
7
12
8
6
8
5
6
6
8
6
6
7
7
9
6
9
7
8
24
91
89
92
87
89
93
90
91
84
77
85
76
89
93
84
88
92
90
91
88
89
84
91
78
86
45
88
83
¯
213-216 (215-217)22
226-228 (228-231)22
227-230 (230-232)22
221-224 (225-226)20
219-222 (221-224)23
203-205 (206-208)22
169-171 (169-171)30
183-185 (183-185)28
173-175 (173-175)28
165-168 (166-168)28
182-184 (187-188)20
194-196 (194-195)23
175-177 (178)10
2
3
4-Br
4-OMe
4-OMe
4-Me
4-Me
4-F
Me
Me
Et
4c
4
4d
5
4e
6
Me
Et
4f
7
4g
8
Et
4h
9
3,4-di-Cl
H
Et
4i
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
Et
4j
H
Me
Me
Me
Me
Me
Me
Me
Et
4k
4-Cl
4-Br
H
4l
4m
4n
180-182 (180)10
4-F
4-OMe
4-Me
H
4o
200-202 (204-205)23
200-202 (200-202)33
168-170 (169-171)20
170-173 (174-175)20
197-199 (196-198)30
178-181 (179-181)28
216-218 (220-221)23
185-188 (190)10
190-191 (189-191)20
158-161 (160-163)10
166-168 (164-167)29
235-237 (239-241)22
194-196 (194-196)29
218-220 (219-222)27
¯
4-F
4p
H
4q
H
H
4r
H
4-Br
4-OMe
H
Et
4s
H
Et
4t
3-Cl
3-Cl
4-Cl
4-Br
3-Br
4-NO2
H
Me
Et
4u
4-Cl
H
4v
Me
Me
Et
4w
4x
4-Cl
H
4y
H
Me
Et
4z
4-Me
4-F
4aa
4ab
No reaction
4-Cl
4-NMe2
Et
4-OMe
Me
[a] Isolated yield. [b] The references of known products in the literature.
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138.0, 138.4, 142.2, 143.3, 146.0, 155.4 (C-4), 168.1 (C=O).
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J. Chin. Chem. Soc. 2013, 60, 355-358