Al(H2PO4)3 as an efficient and reusable catalyst for the multi-component synthesis of highly functionalized piperidines and dihydro-2-oxypyrroles

Article abstract of DOI:10.1007/s13738-013-0222-8

Extremely facile and efficient procedures have been developed for the synthesis of highly functionalized piperidines and dihydro-2-oxypyrroles via one-pot multi-component reactions in the presence of Al(H₂PO ₄)₃ as a heterogeneous and eco-friendly catalyst under mild conditions. The multi-component reaction of aromatic aldehydes, aromatic amines, and β-keto esters catalyzed by Al(H₂PO₄) ₃ in EtOH at room temperature provides highly functionalized piperidines in good to excellent yields. The structure as well as the relative stereochemistry of these functionalized piperidines was confirmed by single X-ray crystallographic analysis. The same catalyst was found useful for the synthesis of polyfuntionalized dihydro-2-oxypyrroles using a four-component reaction of amines, dialkyl acetylenedicarboxylates and formaldehyde in MeOH at ambient temperature. It is found that the catalyst is recyclable and can be used up to five times without significant loss of its activity.

Full text of DOI:10.1007/s13738-013-0222-8

J IRAN CHEM SOC
DOI 10.1007/s13738-013-0222-8
ORIGINAL PAPER
Al(H2PO4)3 as an efficient and reusable catalyst for the
multi-component synthesis of highly functionalized
piperidines and dihydro-2-oxypyrroles
•
Seyed Sajad Sajadikhah Nourallah Hazeri Malek Taher Maghsoodlou
•
•
•
Sayyed Mostafa Habibi-Khorassani Adel Beigbabaei Anthony C. Willis
•
Received: 16 August 2012 / Accepted: 17 January 2013
Ó Iranian Chemical Society 2013
Abstract Extremely facile and efficient procedures have
been developed for the synthesis of highly functionalized
piperidines and dihydro-2-oxypyrroles via one-pot multi-
component reactions in the presence of Al(H2PO4)3 as a
heterogeneous and eco-friendly catalyst under mild con-
ditions. The multi-component reaction of aromatic alde-
hydes, aromatic amines, and b-keto esters catalyzed by
Al(H2PO4)3 in EtOH at room temperature provides highly
functionalized piperidines in good to excellent yields. The
structure as well as the relative stereochemistry of these
functionalized piperidines was confirmed by single X-ray
crystallographic analysis. The same catalyst was found
useful for the synthesis of polyfuntionalized dihydro-2-
oxypyrroles using a four-component reaction of amines,
dialkyl acetylenedicarboxylates and formaldehyde in
MeOH at ambient temperature. It is found that the catalyst
is recyclable and can be used up to five times without
significant loss of its activity.
Keywords Heterocycle ꢀ Piperidine ꢀ Dihydro-2-
oxypyrrole ꢀ Multi-component reaction ꢀ Reusable catalyst ꢀ
Al(H2PO4)3
Introduction
The design of novel multi-component reactions (MCRs) has
received great attention from research groups in medicinal
chemistry, drug discovery and materials science due to their
significant advantages over conventional linear-type synthe-
ses, including simple procedures, environmental friendliness,
atom economy, and the ability to generate architecturally
complex molecules in one synthetic step [1, 2].
Polyfunctionalized heterocyclic compounds are playing
important roles in drug discovery processes and in the
analysis of drugs. In particular, piperidines and their
analogues have been receiving attention owing to their
biological activities [3, 4], such as antimalarial [5], antihy-
pertensive [6], antibacterial [7], anticonvulsant, and anti-
inflammatory agents [8]. Also, substituted piperidines have
been established as therapeutic agents such as clebopride,
cisapride, bamipine, fentanyl, a-methylfentanyl, and indor-
amine [9]. To date, methods for the synthesis of function-
alized piperidines have been reported using MCRs in the
presence of L-proline/TFA [5], InCl3 [10, 11], bro-
modimethylsulfonium bromide (BDMS) [12], tetrabutyl-
ammonium tribromide (TBATB) [13], iodine [14], cerium
ammonium nitrate (CAN) [15], ZrOCl2ꢀ8H2O [16], picric
acid [17], BF3ꢀSiO2 [18], and FeCl3/SiO2 nano particles [19].
On the other hand, the ubiquity of pyrrol-2-ones in phar-
maceuticals and natural products makes them attractive tar-
gets for organic synthesis. Pyrrol-2-one and its derivatives
are key compounds for the synthesis of bioactive molecules
such as Chaetoglobosin A and C [20], and Clausenamide
Electronic supplementary material The online version of this
article (doi:10.1007/s13738-013-0222-8) contains supplementary
material, which is available to authorized users.
S. S. Sajadikhah ꢀ N. Hazeri (&) ꢀ M. T. Maghsoodlou ꢀ
S. M. Habibi-Khorassani
Department of Chemistry, Faculty of Science,
University of Sistan and Baluchestan,
P. O. Box 98135-674, Zahedan, Iran
e-mail: nhazeri@chem.usb.ac.ir
A. Beigbabaei
The Institute of Standards and Industrial Research of Iran
(ISIRI), Tehran, Iran
A. C. Willis
Research School of Chemistry, The Australian National
University, Canberra, ACT 0200, Australia
123

J IRAN CHEM SOC
[21]. Moreover, dihydro-2-oxypyrrols have been success-
fully used as HIV integrase [22], herbicidal [23], pesticides
[24], anti-tumor and anticancer agents [25], mitomycin
antibiotics [26], and also inhibitor of DNA polymerase [27].
As a result, tremendous progress has been made in accessing
substituted pyrrol-2-ones, some of which rely on multistep
routes [28–31]. Recently, multi-component reactions have
been used for one-pot synthesis of dihydropyrrol-2-ones
using catalysts such as AcOH [32], and I2 [33]. However,
owing to the importance of piperidines and dihydropyrrol-2-
ones from pharmaceutical and biological view points, there is
still the need to develop efficient, mild, and environmentally
benign protocols for the synthesis of these heterocycles.
During the past decade, the use of solid acidic catalysts
has received considerable attention in organic synthesis
due to their important advantages such as environmental
compatibility, reusability, low cost, non-toxicity, opera-
tional simplicity, ease of handling, and isolation from the
reaction mixture. In this respect, aluminum tris(dihydrogen
phosphate) [Al(H2PO4)3] is well known as an efficient
heterogeneous catalyst for organic synthesis [34–39].
In this article, we report simple and efficient procedures
for the synthesis of various highly functionalized piperidines
and dihydro-2-oxypyrroles under mild reaction conditions.
ambient temperature. The catalyst thus prepared was finally
transferred and stored in an air tight sample vial [34, 35].
General procedure for synthesis of highly
functionalized piperidine 4
First, a solution of aromatic amine 2 (2 mmol) and
b-ketoester 3 (1 mmol) in EtOH (5 mL) was stirred for
30 min in the presence of Al(H2PO4)3 (0.2 g) at ambient
temperature. Next, the aromatic aldehyde 1 (2 mmol) was
added and the reaction mixture was allowed to stir for the
appropriate time. After completion of the reaction as
monitored by TLC, the solid material was filtered off, dried,
and then dissolved in acetone or CH2Cl2 (10 mL). The
catalyst was filtered and the solvent was evaporated under
vacuum. The obtained solid was washed with EtOH
(3 9 2 mL) to give the pure product 4. Physical and spec-
tral data for selected products are represented below.
Ethyl 2,6-bis(4-methoxyphenyl)-1-phenyl-4-(phenylamino)-
1,2,5,6-tetrahydropyridine-3-carboxylate (4n)
White solid; IR (KBr, cm-1) m = 3,270 (NH), 1,656 (C=O);
1H NMR (400 MHz, CDCl3): d = 1.50 (t, J = 7.2 Hz, 3H,
OCH2CH3), 2.82 (dd, J = 15.2, 2.4 Hz, 1H, H0-5), 2.91 (dd,
J = 15.2, 5.6 Hz, 1H, H00-5), 3.82 (s, 3H, OCH3), 3.83 (s,
3H, OCH3), 4.39 (dq, J = 10.8, 7.2 Hz, 1H, OCHaHb), 4.52
(dq, J = 10.8, 7.0 Hz, 1H, OCHaHb), 5.13 (d, J = 2.8 Hz,
1H, H-6), 6.40 (d, J = 6.8 Hz, 2H, ArH), 6.42 (s, 1H, H-2),
6.57 (d, J = 8.4 Hz, 2H, ArH), 6.65 (t, J = 7.2 Hz, 1H,
ArH), 6.84–6.88 (m, 4H, ArH), 7.09–7.29 (m, 9H, ArH),
10.35 (s, 1H, NH); 13C NMR (100 MHz, CDCl3): d = 14.6
(OCH2CH3), 33.8 (C-5), 54.5 (C-2), 55.2 (OCH3), 55.3
(OCH3), 57.5 (C-6), 59.6 (OCH2CH3), 98.4 (C-3), 113.1,
113.6, 114.0, 116.2, 125.6, 125.7, 127.5, 127.7, 128.9, 134.8,
136.2, 138.0, 147.1, 156.1 (C-4), 158.1, 158.5, 168.4 (C=O);
MS (EI, 70 eV) m/z (%): 534 (M?, 13), 461 (4), 427 (41),
322 (80), 211 (79), 210 (100), 134 (5), 104 (5), 77 (41).
Crystallographic data (excluding structure factors) for the
structure in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
CCDC 855712 for 4n. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK (fax: ?44-1223-336033 or e-mail:
deposit@ccdc.cam.ac.uk), or via www.ccdc.cam.ac.uk/data
request/cif.
Experimental
General
Melting points and IR spectra were obtained on an Elec-
trothermal 9100 apparatus and a JASCO FT/IR-460 plus
1
spectrometer, respectively. The H and 13C NMR spectra
were recorded on a Bruker DRX-400 Avanve instrument
with CDCl3 as solvent at 400 and 100 MHz, respectively.
The mass spectra were recorded on an Agilent Technology
(HP) mass spectrometer, operating at an ionization potential
of 70 eV. Elemental analyses for C, H, and N were per-
formed using a Heraeus CHN–O-Rapid analyzer. All
chemicals were purchased from Merck (Darmastadt, Ger-
many), Acros (Geel, Belgium) and Fluka (Buchs, Switzer-
land), and used without further purification.
Preparation of the catalyst Al(H2PO4)3
The catalyst was prepared by taking a mixture of alumina
(neutral) and concentrated phosphoric acid (88 %) in a
silica boat, maintaining the molar ratio of alumina–H3PO4
as 1:3, and heating at 200–220 °C in a hot sand bath. The
mixture was stirred at the stipulated temperature until the
swampy mass solidified, and then the temperature was
lowered to around 100 °C. The whole solidified product
was then placed in a vacuum desiccator and cooled to
Ethyl 4-(4-methoxyphenylamino)-2,6-bis(3-bromophenyl)-
1-(4-methoxyphenyl)-1,2,5,6-tetrahydropyridine-3-
carboxylate (4p)
White solid; mp: 198–200 °C; IR (KBr, cm-1) m = 3,324
(NH), 1,655 (C=O); 1H NMR (400 MHz, CDCl3):
123

J IRAN CHEM SOC
d = 1.48 (t, J = 7.2 Hz, 3H, OCH2CH3), 2.65 (dd,
J = 15.2, 2.4 Hz, 1H, H0-5), 2.78 (dd, J = 15.2, 5.4 Hz,
1H, H00-5), 3.71 (s, 3H, OCH3), 3.80 (s, 3H, OCH3),
4.30–4.34 (m, 1H, OCHaHb), 4.47–4.52 (m, 1H, OCHaHb),
5.03 (br s, 1H, H-6), 6.29 (d, J = 7.6 Hz, 2H, ArH), 6.32
(s, 1H, H-2), 6.42 (d, J = 9.2 Hz, 2H, ArH), 6.71 (d,
J = 9.2 Hz, 2H, ArH), 6.74 (d, J = 8.8 Hz, 2H, ArH),
7.09–7.29 (m, 4H, ArH), 7.37 (d, J = 7.6 Hz, 1H, ArH),
7.43 (d, J = 7.6 Hz, 1H, ArH), 7.55 (s, 1H, ArH), 10.16 (s,
1H, NH); 13C NMR (100 MHz, CDCl3): d = 14.9
(OCH2CH3), 33.5 (C-5), 55.4 (OCH3), 55.6 (OCH3), 57.5
(C-6), 59.7 (OCH2CH3), 96.4 (C-3), 114.1, 114.3, 114.6,
122.6, 122.7, 125.2, 125.4, 128.1, 129.5, 129.6, 129.7,
129.9, 130.3, 130.4, 130.5, 140.8, 145.5, 146.9, 151.4,
156.6 (C-4), 158.1, 167.9 (C=O); MS (EI, 70 eV): m/z
(%) = 696 (M?4, 3), 694 (M?2, 5), 692 (M?, 3), 568 (8),
402 (100), 328 (30), 290 (68), 275 (46), 167 (20), 77 (10);
Anal. Calcd for C34H32Br2N2O4: C 58.97, H 4.66, N 4.05.
Found: C 59.25, H 4.75, N 4.17.
R2
CHO
NH
4
O
2
2
O
O
3
OR3
R1
Al(H2PO4)3
EtOH, r.t.
5
6
OR3
1
+
NH2
2
N1
3
R1
R1
R2
2
R2
4
Scheme 1 Synthesis of highly funtionalized piperidine 4
filtered and the solvent was evaporated under vacuum. The
obtained solid was washed with EtOH (3 9 2 mL) to give
the pure product 9.
Ethyl 4-(4-methoxyphenylamino)-1-(4-methoxyphenyl)-2,5-
dihydro-5-oxo-1H-pyrrole-3-carboxylate (9h)
Pall yellow solid; mp: 152–154 °C; IR (KBr, cm-1
)
m = 3,264 (NH), 1,692, 1,640 (2C=O); 1H NMR
(400 MHz, CDCl3): d = 1.26 (t, J = 7.2 Hz, 3H,
OCH2CH3), 3.82 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 4.23
(q, J = 7.2 Hz, 2H, OCH2CH3), 4.49 (s, 2H, CH2–N), 6.87
(d, J = 9.2 Hz, 2H, ArH), 6.93 (d, J = 9.2 Hz, 2H, ArH),
7.12 (d, J = 8.8 Hz, 2H, ArH), 7.69 (d, J = 9.2 Hz, 2H,
ArH), 8.03 (s, 1H, NH); 13C NMR (100 MHz, CDCl3):
d = 14.3 (OCH2CH3), 48.4 (CH2–N), 55.4 (OCH3), 55.5
(OCH3), 60.1 (OCH2CH3), 101.3, 113.5, 114.2, 120.9,
124.8, 131.7, 132.0, 143.7, 156.8, 157.0, 163.5 (C=O),
Methyl 4-(p-tolylamino)-2,6-diphenyl-1-p-tolyl-1,2,5,6-
tetrahydropyridine-3-carboxylate (4q)
White solid; mp: 190–192 °C; IR (KBr, cm-1) m = 3,310
(NH), 1,650 (C=O); 1H NMR (400 MHz, CDCl3):
d = 2.20 (s, 3H, CH3), 2.30 (s, 3H, CH3), 2.78 (dd,
J = 15.2, 2.4 Hz, 1H, H0-5), 2.88 (dd, J = 15.2, 6.0 Hz,
1H, H00-5), 3.96 (s, 3H, OCH3), 5.16 (d, J = 3.6 Hz, 1H,
H-6), 6.20 (d, J = 8.4 Hz, 2H, ArH), 6.46 (s, 1H, H-2),
6.48 (d, J = 8.8 Hz, 2H, ArH), 6.92 (t, J = 8.0 Hz, 4H,
ArH), 7.20–7.31 (m, 10H, ArH), 10.22 (s, 1H, NH); 13C
NMR (100 MHz, CDCl3): d = 20.1 (CH3), 20.9 (CH3),
33.6 (C-5), 50.9 (OCH3), 55.2 (C-2), 58.2 (C-6), 97.5 (C-
3), 112.9, 125.1, 126.0, 126.2, 126.4, 126.7, 127.1, 128.2,
128.6, 129.4, 135.2, 135.6, 143.0, 144.3, 144.8, 156.6 (C-
4), 168.6 (C=O); MS (EI, 70 eV): m/z (%) = 488 (M?,
28), 429 (9), 411 (91), 379 (37), 322 (29), 292 (81), 194
(80), 104 (19), 91 (100), 77 (37), 59 (11); Anal. Calcd for
C33H32N2O2: C 81.12, H 6.60, N 5.73. Found: C 81.33, H
6.68, N 5.84.
Table 1 Optimization of the reaction conditions for the synthesis 4a
CHO
NH
N
O
2
O
O
Al(H2PO4)3
r.t.
OMe
Me
+
OMe
NH2
2
Me
Me
Entry
Solvent
Catalyst (g)
Time (h)
Yield (%)a
1
EtOH
MeOH
CH2Cl2
EtOAc
MeCN
EtOH
EtOH
EtOH
EtOH
EtOH
MeOH
EtOH
0.05
0.05
0.05
0.05
0.05
0.1
12
12
12
12
12
12
11
10
10
10
10
24
57
54
38
35
46
74
83
87
84
80
85
–
2
General procedure for synthesis of highly
3
functionalized dihydro-2-oxypyrrole 9
4
5
A mixture of amine 5 (1 mmol) and dialkyl acetylenedicar-
boxylate 6 (1 mmol) in methanol (3 mL) was stirred for
20 min. Next, aromatic amine 7 (1 mmol), formaldehyde 8
(1.5 mmol), and Al(H2PO4)3 (0.1 g) were added succes-
sively. The reaction mixture was allowed to stir at ambient
temperature for the appropriate time (see Table 5). The
progress of the reaction was monitored by TLC. After
completion, the solid material was separated, dried, and then
dissolved in acetone or CHCl3 (10 mL). The catalyst was
6
7
0.15
0.2
8
9
0.25
0.3
10
11
12
a
0.2
No catalyst
Yield of isolated product
123

J IRAN CHEM SOC
164.8 (C=O); Anal. Calcd for C21H22N2O5: C 69.96, H
5.80, N 7.33. Found: C 70.14, H 5.89, N 7.30.
1.42 (sextet, J = 7.2 Hz, 2H, CH2), 1.64 (quintet,
J = 7.2 Hz, 2H, CH2), 3.82 (s, 3H, OCH3), 3.85 (t,
J = 7.2 Hz, 2H, CH2–NH), 4.45 (s, 2H, CH2–N), 6.85 (br,
1H, NH), 7.18 (d, J = 7.6 Hz, 1H, ArH), 7.40 (d,
Methyl 4-(benzylamino)-1-(4-fluorophenyl)-2,5-dihydro-5-
oxo-1H-pyrrole-3-carboxylate (9l)
J = 7.6 Hz, 2H, ArH), 7.73 (d, J = 7.6 Hz, 2H, ArH); 13
C
NMR (100 MHz, CDCl3): d 13.9 (CH3), 19.9(CH2), 33.3
(CH2), 42.7 (CH2–NH), 47.7 (CH2–N), 51.0 (OCH3), 96.1,
118.4, 125.2, 128.8, 138.4, 164.5 (C=O), 165.6 (C=O).
White solid; mp: 166–168 °C; IR (KBr, cm-1) m = 3,316
(NH), 1,700, 1,644 (2C=O); H NMR (400 MHz, CDCl3):
1
d = 3.80 (s, 3H, OCH3), 4.42 (s, 2H, CH2–N), 5.13 (d,
J = 6.4 Hz, 2H, CH2–NH), 8.90 (br s, 1H, NH), 7.09–7.13
(m, 2H, ArH), 7.29–7.38 (m, 5H, ArH), 7.72–7.75 (m, 2H,
ArH); 13C NMR (100 MHz, CDCl3): d = 46.5 (CH2–NH),
48.2 (CH2–N), 51.1 (OCH3), 97.3, 115.1 (d, J = 22.0 Hz),
115.7, 116.0, 121.1 (d, J = 8.0 Hz), 125.1 (d, J = 8.0 Hz),
127.4, 127.5, 128.7, 134.8 (d, J = 8.0 Hz), 139.4, 159.8 (d,
J = 243.0 Hz), 164.3 (C=O), 165.4 (C=O); MS (EI, 70 eV):
m/z (%) = 340 (M?, 51), 325 (14), 308 (30), 281 (26), 279
(37), 201 (9), 177 (10), 142 (10), 122 (18), 105 (10), 95 (20),
91 (100), 65 (21); Anal. Calcd for C19H17FN2O3: C 67.05, H
5.03, N 8.23. Found: C 67.33, H 5.15, N 8.40.
Methyl 4–(butylamino)-1-(3,4-dichlorophenyl)-2,5-
dihydro-5-oxo-1H-pyrrole-3-carboxylate (9p)
White solid; mp: 97–99 °C; IR (KBr, cm-1) m = 3,335
(NH), 2,933, 2,853, 1,711, 1,642 (2C=O); 1H NMR
(400 MHz, CDCl3): d = 0.97 (t, J = 7.2 Hz, 3H, CH3),
1.44 (sextet, J = 7.2 Hz, 2H, CH2), 1.63 (quintet,
J = 7.2 Hz, 2H, CH2), 3.82 (s, 3H, OCH3), 3.87 (2H, t,
J = 7.2 Hz, CH2–NH), 4.39 (s, 2H, CH2–N), 6.75 (br s,
1H, NH), 7.46 (d, J = 8.8 Hz, 1H, ArH), 7.67 (dd, J = 9.0,
2.8 Hz, 1H, m, ArH), 8.00 (d, J = 2.8 Hz, 1H, ArH); 13C
NMR (100 MHz, CDCl3): d = 13.8 (CH3), 19.8 (CH2),
33.3 (CH2), 42.6 (CH2–NH), 47.6 (CH2–N), 51.0 (OCH3),
96.1, 117.9, 120.5, 128.1, 130.5, 133.0, 138.2, 144.0, 164.5
(C=O), 165.5 (C=O); MS (EI, 70 eV): m/z (%) = 358
(M?2, 37), 356 (M?, 57), 341 (8), 315 (51), 313 (78), 299
(55), 297 (100), 283 (52), 281 (78), 241 (16), 213 (13), 187
Methyl 4-(butylamino)-1-phenyl-2,5-dihydro-5-oxo-1H-
pyrrole-3-carboxylate (9n)
1
White solid, mp: 61–63 °C (lit. mp: 60 °C) [33]; H NMR
(400 MHz, CDCl3): d = 0.97 (t, J = 7.2 Hz, 3H, CH3),
Table 2 Synthesis of highly substituted piperidine 4a–t
Entry
R1
R2
R3
Product
Time (h)
Yield (%)a
M.p. (°C)
Lit. M.p. (°C) [Ref]b
1
4-Me
4-Me
4-F
H
Me
Et
4a
4b
4c
4d
4e
4f
10
10
10
10
12
16
12
12
14
10
10
11
12
12
10
14
10
10
10
10
87
85
84
85
79
32
80
80
74
77
82
80
76
83
81
79
78
79
82
80
214–217
228–230
192–194
188–190
178–181
238–240
190–192
198–201
159–161
228–231
204–205
126–128
160–162
166–168
204–206
198–200
190–192
183–185
165–167
200–202
215–217 [12]
228–231 [12]
193–195 [14]
189–191 [10]
180 [5]
2
H
3
H
Me
Me
Me
Me
Me
Et
4
4-Cl
4-OMe
4-NO2
H
H
5
H
6
H
239–241 [5]
194 [5]
7
H
4g
4h
4i
8
H
4-Cl
4-OMe
4-Br
4-Me
H
202 [5]
9
3-Cl
4-Me
4-Me
3-Me
4-Br
4-OMe
4-Me
3-Br
H
Me
Me
Me
Me
Me
Et
160 [5]
10
11
12
13
14
15
16
17
18
19
20
a
4j
230–232 [12]
206–208 [12]
131–134 [15]
159–160 [15]
166–168 [41]
204–206 [42]
–
4k
4l
4-Cl
H
4m
4n
4o
4p
4q
4r
4s
4-Cl
4-OMe
4-Me
4-F
H
Me
Et
Me
Et
–
4-Me
3-Br
4-F
183–185 [41]
164–167 [42]
200–202 [41]
Et
4-Me
Me
4t
Yield of isolated product
b
The references of known products in the literature
123

J IRAN CHEM SOC
13), 172 (23), 145 (15), 112 (17), 97 (20), 81 (39), 69 (75),
55 (60); Anal. Calcd for C16H18Cl2N2O3: C 53.79, H 5.08,
N 7.84. Found: C 53.97, H 5.21, N 7.93.
products 4 in good to high yields. However, p-nitro benz-
aldehyde gives the corresponding product in low yield
(Table 2, Entry 7), which is caused by the formation of
more stable imine due to extra conjugation in the presence
of a nitro group, which is less reactive [14].
Results and discussion
All known products have been reported previously in the
literature and were characterized by comparison of IR and
In continuation of our work on heterocycles synthesis,
especially synthesis of piperidines [40–42], herein, we
employed Al(H2PO4)3 as an efficient and recyclable het-
erogeneous catalyst for the one-pot three (in situ five)-
component synthesis of highly functionalized piperidines
in EtOH at ambient temperature (Scheme 1).
˚
Table 3 Selected bond lengths (A), bond angles (°), and torsion
angles (°) in piperidine structure 4n
First, the reaction between 4-methylbenzaldehyde
(2 mmol), aniline (2 mmol) and methyl acetoacetate
(1 mmol) was carried out in the presence of Al(H2PO4)3
(0.05 g) in EtOH at ambient temperature. The reaction
proceeds smoothly to generate the corresponding highly
substituted piperidine 4a in 57 % yield after 12 h. In order
to optimize the reaction conditions, this reaction was
considered as the model (Table 1). The best result was
achieved in the presence of 0.2 g of Al(H2PO4)3 in EtOH at
ambient temperature (Table 1, Entry 8). To illustrate the
need for catalytic amounts of Al(H2PO4)3 in these reac-
tions, the model reaction was also studied in the absence of
the catalyst in EtOH, where no product was obtained at
room temperature even after 24 h (Table 1, Entry 12).
Using the optimized reaction conditions, a series of
highly substituted piperidines were prepared in good to high
yields from the reaction between aromatic aldehydes, ani-
lines, and methyl/ethyl acetoacetate in the presence of
Al(H2PO4)3 as a catalyst. As indicated in Table 2, benzal-
dehyde and its derivatives containing electron withdrawing
and/or electron donating groups reacted efficiently with
aniline and substituted anilines to give the corresponding
˚
Length (A)
Entry
Bond
1
2
3
4
5
6
C101–C102
C102–C103
C103–N104
N104–C105
C105–C106
C106–C101
1.3682(16)
1.5191(16)
1.4674(14)
1.4638(14)
1.5445(16)
1.5026(16)
Entry
Atom1
Atom2
Atom3
Angle (°)
1
2
3
4
5
6
C102
C101
C102
C103
N104
C105
C101
C102
C103
N104
C105
C106
C106
C103
N104
C105
C106
C101
115.65 (10)
117.74 (10)
109.96 (9)
119.73 (9)
109.83 (9)
110.50 (9)
Entry
Atom1
Atom2
Atom3
Atom4
Angle (°)
1
2
3
4
5
6
7
8
9
C101
C101
C101
C102
C102
C103
C103
C105
C106
C102
C106
C106
C101
C103
N104
C102
C106
C101
C103
C105
C105
C106
N104
C105
C101
C101
C102
N104
N104
C151
C105
C105
C106
C106
N111
C121
44.1 (2)
51.0 (1)
-75.4 (1)
-48.9 (1)
-39.7 (2)
-6.5 (1)
0.2 (2)
133.2 (1)
-178.7 (1)
Fig. 1 ORTEP of the X-ray structure of piperidine 4n
123

J IRAN CHEM SOC
R2
R2
R2
NH
O
1
3
N
O
N
N
O
OR3
inter-molecular
Mannich reaction
OR3
R1
Al(H2PO4)3
OR3
R1
A
1
2
R1
HN
R1
N
R2
R2
R2
B
C
D
R2
R2
R2
H
N
N
O
N
O
NH
N
O
OR3
OR3
R1
OR3
R1
intra-molecular
Mannich reaction
Al(H2PO4)3
Al(H2PO4)3
N
R1
R1
R1
R1
R2
R2
R2
4
F
E
Scheme 2 Proposed mechanism for the synthesis of highly functionalized piperidine 4
Scheme 3 Synthesis of highly
substituted dihydro-2-
oxypyrrole 9
CO2R2
O
H
N
R1
Al(H2PO4)3 (0.1 g)
MeOH, r.t.
R1 NH2
+
+
CH2O
+
Ar NH2
N Ar
R2O2C
CO2R2
5
7
9
6
8
NMR spectra with authentic samples. The structures of new angels, and torsion angels for compound 4n are exhibited in
1
compounds 4p,q were deduced on the basis of IR, H and Table 3.
13C NMR spectroscopy, mass spectrometry, and elemental
On the basis of the previous literature [12–15, 40–42], the
analysis. For example, the mass spectrum of 4p displayed proposed mechanism for the formation of piperidine 4 is
the molecular ion peak (M?) at m/z = 692, which is con- illustrated in Scheme 2. First, b-ketoester 3 and aldehyde 1
sistent with the proposed structure. The 1H NMR spectrum react with aniline 2 in the presence of Al(H2PO4)3 to give
of 4p exhibited two doublets of doublets at d = 2.65
(J = 15.2, 2.4 Hz) and d = 2.78 (J = 15.2, 5.4 Hz) for the
CH2 protons of the piperidine ring (H0- H00-5). The methoxy
Table 4 Optimization of the reaction conditions for the synthesis 9a
groups appeared as two singlets at d = 3.71 and 3.80 ppm,
respectively. The ethoxy protons were observed as a triplet
at 1.48 ppm (J = 7.2 Hz) and two multiplets at
4.30–4.52 ppm. One of the methine protons of the piperi-
dine ring (H-6) was observed as a broad singlet at d
5.03 ppm, and another methine proton (H-2) appeared as a
singlet at d 6.32 ppm. The resonances of aromatic protons
were observed as mixture of singlet, doublets, and multiplet
at d 6.29–7.55 ppm. The NH proton was observed as a
singlet at d 10.16 ppm, thus indicating an intramolecular
synthesis 9a
CO2Me
NH2
NH2
O
H
N
Al(H2PO4)3
r.t.
+
+ CH2O
+
N
CO2Me
MeO2C
Entry
Solvent
Catalyst (g)
Time (h)
Yield (%)a
1
2
3
4
5
6
7
8
a
EtOH
0.05
7
5
65
MeOH
EtOAc
MeCN
MeOH
MeOH
MeOH
MeOH
0.05
73
0.05
10
9
34
0.05
59
H-bond formation with the vicinal carbonyl group. The 13
C
0.1
5
81
NMR spectrum 4p exhibited 29 distinct signals in agree-
ment with the proposed structure. Furthermore, the structure
as well as the relative stereochemistry of piperidine 4, for
example 4n was further confirmed by single X-ray crys-
tallographic analysis (Fig. 1). Selected bond length, bond
0.15
5
81
0.2
5
78
No catalyst
24
Trace
Yield of isolated product
123

J IRAN CHEM SOC
Table 5 Synthesis of highly functionalized dihydro-2-oxypyrroles 9a-p
Entry
R1
R2
Ar
Product
Time (h)
Yield (%)a
Mp (°C)
Lit. mp (°C) [Ref]b
1
Ph
Me
Et
Ph
9a
9b
9c
9d
9e
9f
5
5
5
5
6
6
5
6
5
5
6
5
5.5
6
5
5
81
80
82
79
83
81
84
77
79
83
83
80
79
76
82
78
154–155
136–138
177–179
128–130
171–173
175–177
166–168
152–154
124–126
138–140
129–131
166–168
145–147
61–63
155–156 [33]
138–140 [32]
177–178 [33]
131–132 [33]
172–173 [32]
173–174 [33]
169–171 [32]
–
2
Ph
Ph
3
4-Me–C6H4
4-Me–C6H4
4-F–C6H4
4-Cl–C6H4
4-Br–C6H4
4-OMe–C6H4
PhCH2
Me
Et
4-Me–C6H4
4-Me–C6H4
4-F–C6H4
4-Cl–C6H4
4-Br–C6H4
4-OMe–C6H4
4-OMe–C6H4
Ph
4
5
Et
6
Me
Et
7
9g
9h
9i
8
Et
9
Me
Me
Et
129–130 [33]
140–141 [32]
130–132 [32]
–
10
11
12
13
14
15
16
a
PhCH2
9j
PhCH2
Ph
9k
9l
PhCH2
Me
Me
Me
Me
Me
4-F–C6H4
4-Cl–C6H4
Ph
PhCH2
9m
9n
9o
9p
147–148 [33]
60 [33]
n-C4H9
n-C4H9
4-Br–C6H4
3,4-Cl2–C6H3
109–111
97–99
108–109 [33]
–
n-C4H9
Isolated yield
b
References refer to known products as mentioned in the literature
R1
CO2R2
NH
R2O2C
OR2
O
R1 NH2
O
+
O
H
N
N
OR2
R1
N
O
R1
R2O2C
CO2R2
R1
G
5
N
Ar
H
N
Ar
6
R2O2C
R2O2C
Al(H2PO4)3
HN
Ar
9
Al(H2PO4)3
N
I
Ar NH2
+
CH2O
J
Ar
7
8
H
Scheme 4 Suggested mechanism for the synthesis of polyfunctionalized dihydro-2-oxypyrrole 9
enamine A and imine B, respectively. Next, the reaction
between enamine A and imine B leads to intermediate
C through intermolecular Mannich-type reaction. The inter-
mediate C reacts with aldehyde 1 to generate intermediate
D. Then, tautomerization of D generates intermediate E,
which immediately undergoes intramolecular Mannich-type
reaction to produce intermediate F. In the final step, tauto-
merization of the intermediate F generates the desired
piperidine 4 due to conjugation with the ester group.
Motivated from the efficient catalytic activity of
Al(H2PO4)3 for the synthesis of highly functionalized
piperidines, we explored its catalytic activity for the syn-
thesis of polyfunctionalized dihydro-2-oxypyrroles 9 via
one-pot four-component reaction of amines, dialkyl acet-
ylenedicarboxylates and formaldehyde at room tempera-
ture (Scheme 3).
was performed using different quantities of Al(H2PO4)3 in
different solvents at ambient temperature (Table 4). The use
of 0.1 g of catalyst in MeOH resulted in the highest yield in
5 h (Table 4, Entry 5). Note that a control experiment
showed that product 9a was obtained only in trace yield
Table 6 Reusability of Al(H2PO4)3 in the synthesis of compounds 4a
and 9a
Run no.
Compound 4a
Compound 9a
Time (h)
Yield (%)a
Time (h)
Yield (%)a
1
2
3
4
5
a
10
10
10
12
14
87
86
84
81
80
5
5
5
6
6
81
81
79
74
75
To find the optimal conditions, the reaction of aniline,
dimethyl acetylendicarboxylate (DMAD), and formaldehyde
Isolated yield
123

J IRAN CHEM SOC
also reaction of amine 7 whit formaldehyde 8, give inter-
mediate G and imine H, respectively. Attack of G on
H leads to intermediate I, which converts to intermediate
J by intamolecular cyclization. In the final step, tauto-
merization of intermediate J produces the corresponding
dihydeo-2-oxypyrrole 9.
Table 7 Comparison result of Al(H2PO4)3 with the reported catalysts
in literature for the synthesis of highly functionalized piperidines 4a
and 4 g and dihydro-2-oxypyrrole 9b
Compound Catalyst/conditions
Time
(h)
Yield
(%)
Ref.
4a
InCl3/CH3CN, r.t.
BDMS/CH3CN, r.t.
TBATB/EtOH, r.t.
I2/MeOH, r.t.
24
3
50
80
78
84
85
89
81
[10]
[12]
[13]
[14]
[15]
[41]
[40]
The reusability of the catalyst is an important factor
from an economical and environmental point of views and
has attracted much attention in recent years. Thus, the
reusability of Al(H2PO4)3 was examined in the synthesis of
highly functionalize piperidine 4a and dihydro-2-oxypyr-
role 9a as two examples. Since Al(H2PO4)3 is a heteroge-
neous catalyst, it was separated and reused after being
washed with CHCl3 and dried at 100 °C for 60 min. The
results show that the catalyst can be used up to five times
without significant loss of its activity (Table 6).
10
8
CAN/CH3CN, r.t.
22
7
p-TsOHꢀH2O/EtOH, r.t.
Oxalic acid dihydrate/
EtOH, r.t.
12
Al(H2PO4)3/EtOH, r.t.
10
17
87
70
–
4g
L-proline/TFA/CH3CN,
20-30 °C
InCl3/CH3CN, r.t.
[5]
To compare the applicability of the Al(H2PO4)3 with the
reported catalysts in the literature for the synthesis of
highly functionalized piperidines and dihydro-2-oxypyr-
roles, we have tabulated the results of these catalysts in
Table 7. As shown in Table 7, Al(H2PO4)3 can act as
effective catalyst with respect to reaction times and yields
of products.
24
3
60
75
74
81
82
80
78
78
[10]
[12]
[13]
[14]
[15]
[16]
[41]
[40]
BDMS/CH3CN, r.t.
TBATB/EtOH, r.t.
I2/MeOH, 55 °C
24
8
CAN/CH3CN, r.t.
20
3.5
10
12
ZrOCl2ꢀ8H2O/EtOH, reflux
p-TsOHꢀH2O/EtOH, r.t.
Oxalic acid dihydrate/
EtOH, r.t.
In conclusion, we have developed simple and efficient
methods for the one-pot multi-component synthesis of
highly functionalize piperidines and dihydro-2-oxypyrroles
using Al(H2PO4)3 as catalyst under mild reaction condi-
tions. The noteworthy aspects of these procedures are high
atom economy, high to excellent yields, inexpensive and
reusable catalyst, operational simplicity, and lack of need
for complex separation and column chromatography.
Al(H2PO4)3/EtOH, r.t.
AcOH/EtOH, 70 °C
I2/MeOH, r.t.
12
4
80
85
81
80
–
9b
[32]
[33]
–
1
Al(H2PO4)3/MeOH, r.t.
5
when the reaction was examined in the absence of catalyst
(Table 4, Entry 8).
Acknowledgments We gratefully acknowledge financial support
from the Research Council of the University of Sistan and Baluche-
stan and the Australian National University.
Under the optimized reaction conditions, various ani-
lines and dimethyl and/or diethyl acetylenedicarboxylates
were used to test the versatility of this reaction, and the
results have been summarized in Table 5. This protocol
efficiently coupled anilines with electron donating groups
such as Me and OMe, as well as electron withdrawing
groups including F, Cl, and Br to produce the expected
products 9a–h in good to high yields (Table 5, entries 1–8).
Additionally, two different amines were used for the one-
pot four-component synthesis of different highly func-
tionalized dihdro-2-oxypyrroles 5i–p (Table 5, entries
9–16). Aliphatic amines such as benzyl amine and n-butyl
amine reacted smoothly with dialkyl acetylenedicarboxy-
lates, aromatic amines, and formaldehyde to generate the
desired products in high yields. The structures of these
products were also characterized on the basis of IR, 1H, and
13C NMR, Mass spectra and elemental analysis.
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