Al(H2PO4)3 as an efficient and reusable catalyst for one-pot three-component synthesis of α-amino phosphonates under solvent-free conditions

Article abstract of DOI:10.1002/cjoc.201090067

Synthesis of α-amino phosphonates is described under solvent-free conditions at 100 from reaction between aldehydes and amines in the presence of trialkyl phosphites using Al(H₂PO₄)₃ as an efficient and reusable heterogene

Full text of DOI:10.1002/cjoc.201090067

FULL PAPER
Al(H2PO4)3 as an Efficient and Reusable Catalyst for One-pot
Three-component Synthesis of α-Amino Phosphonates
under Solvent-free Conditions
Maghsoodlou, Malek Taher*
Habibi-Khorassani, Sayyed Mostafa
Heydari, Reza
Hazeri, Nourollah
Sajadikhah, Seyed Sajad Rostamizadeh, Mohsen
Department of Chemistry, Faculty of Sciences, University of Sistan and Baluchestan, P. O. Box 98135-674,
Zahedan, Iran
Synthesis of α-amino phosphonates is described under solvent-free conditions at 100 ℃ from reaction between
aldehydes and amines in the presence of trialkyl phosphites using Al(H2PO4)3 as an efficient and reusable heteroge-
neous catalyst. The advantages of this procedure are short reaction time, flexibility and having high to excellent
yields.
Keywords α-amino phosphonate, Al(H2PO4)3, heterogeneous catalyst, aldehyde, trialkyl phosphite
Introduction
help of microwave irradiation. Therefore, it is necessary
to further develop an efficient one-pot multi-component
synthesis of α-amino phosphonates without these prob-
lems.
α-Amino phosphonates are of growing importance in
biological processes, because they are considered to be
structural analogues of the corresponding α-amino acids
and transition state mimics of peptide hydrolysis. In
these connection, the utilities of α-amino phosphonates
as enzyme inhibitors,1 HIV protease,2 anti-therombotic
agents,3 peptide mimics,4 antibiotics,5 herbicides, fungi-
cides, and insecticides,6 as well as the important uses for
antibody generation7 are well documented. As a result,
various methodologies have been developed for the
synthesis of α-amino phosphonates. Many of these
methods are based on nucleophilic addition of phosphite
to imines catalyzed by protic,8 Lewis acids like
BF3•OEt2,9 SnCl4,10 ZnCl2 and MgBr2,11 or by base.12
However, these reactions can not proceed in one-pot
procedure from reaction between an aldehyde, an amine
and a phosphite, because the amines and water that exist
during imine formation can decompose or deactivate the
Lewis acids.13 This drawback has been overcome by
some recent methods using metal triflates [M(OTf)n,
M＝Li, Mg, Al, Cu, Ce],14 InCl3,15 FeCl3,16 Scandium
tris(dodecyl sulfate),17 TaCl5-SiO2,18 lithium perchlo-
rate,19 CF3CO2H,20 In(OTf)3,21 magnesium perchlo-
rate,22 PhNMe3Cl,23 H3PW12O40,24 Amberlyst-15,25
Amberlite-IR 120,26 sulfamic acid,27 TiO2,28 oxalic
acid,29 trifluroethanol,30 microwave assisted,31 ionic
liquid32 and ultrasonic assisted.33 However, some of
these methods displayed drawbacks, such as environ-
mental pollution caused using organic solvent, long re-
action times, expensive catalyst or unavailable reagents,
unsatisfactory yields, complicated operations and the
In the recent years, the use of solid acidic catalysts
has received considerable attention in organic synthesis
due to their important advantages such as, operational
simplicity, environmental compatibility, reusability, low
cost, non-toxic, and ease of preparation, handling and
isolation. Aluminum tris(dihydrogen phosphate) is well
known as an efficient heterogeneous catalyst for organic
synthesis.34,35 In this paper, we report a novel, simple
and efficient procedure for the one-pot three-component
synthesis of α-amino phosphonates from reaction be-
tween aldehydes, amines, and trialkyl phosphites in the
presence of Al(H2PO4)3 as a catalyst under solvent-free
conditions at 100 ℃ (Scheme 1).
Scheme 1 Synthesis of α-amino phosphonates
Experimental
Melting points and IR spectra of all compounds were
measured on an Electrothermal 9100 apparatus and a
1
Shimadzu IR-460 spectrometer respectively. The H,
*
E-mail: mt_maghsoodlou@yahoo.com; Tel.: ＋985412450995; Fax: ＋985412450995
Received June 13, 2009; revised and accepted December 31, 2009.
Chin. J. Chem. 2010, 28, 285— 288
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
285

Maghsoodlou et al.
FULL PAPER
13C and 31P NMR spectra were obtained on BRUKER
DRX-300 and 400 AVANCE instruments with CDCl3
as a solvent. Elemental analyses were performed using a
Heraeus CHN-O-Rapid analyzer. All reagents and sol-
vents obtained from Fluka were used without further
purification.
Al(H2PO4)3 (60 mg) were stirred for a few minutes.
Then trimethyl/triethyl phosphite (1 mmol) was added.
The mixture was stirred at 100 ℃ in oil bath for the
appropriate time (see Table 1). After completion of the
reaction (monitored by TLC), the reaction mixture was
cooled and EtOAc (15 mL) was added to separate the
catalyst by simple filtration. The filtrate was washed
with distilled water (10 mL×3). The organic layer was
dried over anhydrous Na2SO4 and evaporated. The
crude product was purified by silica gel column chro-
matography with the mixture of n-hexane/EtOAc (V∶V
＝7∶3) as an eluant to provide pure α-amino phospho-
nates. Spectral data for the new products are represented
below.
Preparation of Al(H2PO4)3
The catalyst was prepared by taking a mixture of
alumina (neutral) and concentrated phosphoric acid
(88%) in a silica boat maintaining with the molar ratio
of alumina-H3PO4 as 1∶3 and heating at 200—220 ℃
in a hot sand bath. The mixture was stirred at the stipu-
lated temperature until the swampy mass solidified, and
then the temperature was lowered to around 100 ℃.
The whole solidified product was then placed in a vac-
uum desiccator and cooled to ambient temperature. The
catalyst thus prepared was finally transferred and stored
in an air tight sample vial.35
1
Compound 13 Yellow solid, m.p. 92—94 ℃. H
NMR (CDCl3, 400 MHz) δ: 3.66 (d, J＝10.7 Hz, 3H),
3.89 (d, J＝10.7 Hz, 3H), 5.20 (br, 1H), 5.61 (d, J＝
27.1 Hz, 1H), 6.61—6.77 (m, 3H), 6.95—7.01 (m, 1H),
7.10—7.21 (m, 4H); 13C NMR (CDCl3, 100 MHz) δ:
51.75 (d, J＝152.5 Hz), 53.54 (d, J＝7.0 Hz), 54.28 (d,
J＝7.0 Hz), 113.75, 115.50, 119.07, 122.97, 125.64,
129.35, 129.83 (d, J＝2.6 Hz), 129.93 (d, J＝2.6 Hz),
General procedure
The aldehyde (1 mmol), amine (1 mmol) and
Table 1 Synthesis of α-amino phosphonates catalyzed by Al(H2PO4)3
Entry
1
R1
R2
R3
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
H
R4
Time/min
15
Yielda/%
Ref.b
22
28
23
26
26
29
28
25
28
25
22
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Et
95
93
2
90
3
4-NO2-C6H4
4-NO2-C6H4
3-NO2-C6H4
4-Cl-C6H4
Me
Et
5
91
4
50
90
5
Et
55
90
6
Me
Et
12
95
7
4-Cl-C6H4
80
93
8
3-Cl-C6H4
Me
Et
15
90
9
3-Cl-C6H4
85
89
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
4-NMe2-C6H4
4-OH-C6H4
4-F-C6H4
Me
Me
Et
17
93
20
87
80
91
26
c
2-Cl-6-F-C6H3
2,4-di-OMe-C6H3
2,5-di-OMe-C6H3
2-Me-C6H4
4-Me-C6H4
3-NO2-C6H4
4-NO2-C6H4
4-OMe-C6H4
4-OMe-C6H4
4-OMe-C6H4
n-Propyl
Me
Me
Me
Me
Et
5
97
c
c
c
25
97
25
97
30
95
120
70
93
28
21
22
22
21
21
23
29
—
3-NO2-C6H4
4-NO2-C6H4
4-OMe-C6H4
3-NO2-C6H4
4-NO2-C6H4
Ph
Et
91
Me
Me
Et
15
89
35
93
120
130
300
300
300
300
86
Et
90
Me
Me
Me
Et
75
Ph
PhCH2
83
Ph
Et
No reaction
4-OMe-C6H4
H2NCH2CH2
35
28
a Yields refer to the pure isolated products. b All known products have been reported previously in the literature and were characterized by
comparison of IR and NMR spectra with authentic samples. c The new compounds synthesized in this work.
286
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© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2010, 28, 285— 288

Synthesis of α-Amino Phosphonates under Solvent-free Conditions
130.20, 145.77 (d, J＝14.5 Hz); 31P NMR (CDCl3, 161
ceeded smoothly to give the corresponding α-amino
phosphonate in excellent yield (95%) after 15 min (Table
1, Entry 1). With respect to the initial results of first
experiment, several reactions were investigated between
different aldehydes, amines, and trialkyl phosphites in
the presence of Al(H2PO4)3 as a catalyst under sol-
vent-free conditions at 100 ℃. The results are summa-
rized in Table 1. As shown in Table 1, benzaldehydes
with electron-deficient and/or electron-releasing group
reacted efficiently with anilines to give the correspond-
ing α-amino phosphonates in high to excellent yields.
Substituents on the benzene ring such as NO2, NMe2,
OMe, Cl, F, and OH were tolerated during the reaction.
In all cases, the reaction proceeded to afford α-amino
phosphonates exclusively. On the basis of experimental
results, the rate of all reactions in the presence of triethyl
phosphite were reduced in comparison with trimethyl
phosphite under constant conditions. We have also pre-
pared 4 new analogues of these compounds in excellent
yields (Entries 13—16). These new compounds were
characterized by melting point, IR, NMR (1H, 13C and 31P)
and mass spectroscopies.
MHz) δ: 23.00; IR (KBr) ν: －3313 (NH), 1246 (P＝O),
＋
1
1056, 1033 (P—O—Me) cm ; MS m/z (%): 345 (M
＋2, 3), 343 (M＋, 10), 234 (100), 198 (21), 109 (11),
107 (15), 93 (51), 77 (47). Anal. calcd for C15H16ClF-
NO3P: C 52.42, H 4.69, N 4.08; found C 52.62, H 4.71,
N 4.19.
Compound 14 White solid, m.p. 146—148 ℃. 1H
NMR (CDCl3, 400 MHz) δ: 3.48 (d, J＝10.4 Hz, 3H),
3.78 (s, 3H), 3.82 (d, J＝10.4 Hz, 3H), 3.92 (s, 3H),
4.42 (br, 1H), 5.30 (d, J＝24.2 Hz, 1H), 6.46—6.72 (m,
5H), 7.10—7.42 (m, 3H); 13C NMR (CDCl3, 100 MHz)
δ: 47.42 (d, J＝155.9 Hz), 53.67 (d, J＝6.9 Hz), 53.81
(d, J＝6.9 Hz), 55.31, 55.84, 98.55 (d, J＝2.0 Hz),
104.93 (d, J＝2.5 Hz), 113.88, 116.21, 118.49, 129.08
(d, J＝4.7 Hz), 129.55, 145.87 (d, J＝14.7 Hz), 158.17
(d, J＝6.1 Hz), 160.63 (d, J＝2.6 Hz); 31P NMR (CDCl3,
161 MHz) δ: 26.21; IR (KBr) ν: 3290 (NH), 1233 (P＝
－1
O),＋1050, 1027 (P—O—Me) cm ; MS m/z (%): 351
(M , 24), 242 (100), 227 (10), 149 (48), 109 (21), 93
(30), 77 (20). Anal. calcd for C17H22NO5P: C 58.18, H
6.31, N 3.99; found C 58.28, H 6.44, N 3.87.
Compound 15 White solid, m.p. 121—123 ℃. 1H
NMR (CDCl3, 400 MHz) δ: 3.49 (d, J＝10.5 Hz, 3H),
3.73 (s, 3H), 3.82 (d, J＝10.5 Hz, 3H), 3.91 (s, 3H),
4.58 (br, 1H), 5.42 (d, J＝24.5 Hz, 1H), 6.65—6.87 (m,
5H), 7.07—7.14 (m, 3H); 13C NMR (CDCl3, 100 MHz)
δ: 47.99 (d, J＝153.8 Hz), 53.74 (d, J＝7.1 Hz), 53.84
(d, J＝7.1 Hz), 55.66, 56.43, 111.83 (d, J＝1.8 Hz),
113.87, 113.97, 114.06, 118.61, 125.15, 129.16, 145.80
(d, J＝14.3 Hz), 151.46 (d, J＝6.2 Hz), 153.92 (d, J＝
3.3 Hz); 31P NMR (CDCl3, 161 MHz) δ: 25.80; IR
(KBr) ν: 3322 (NH), 1231 (P＝O), 1061, 1040 (P—O—
Me); MS m/z (%): 351 (M＋, 9), 242 (100), 227 (41),
212 (42), 149 (10), 109 (9), 77 (28). Anal. calcd for
C17H22NO5P: C 58.12, H 6.31, N 3.99; found C 58.23,
H 6.44, N 3.90.
The reusability of the catalyst is an important factor
from economical and environmental point of views and
has attracted much attention in recent years. Therefore,
the reusability of aluminum tris(dihydrogen phosphate)
was examined in the reaction between 2,4-dimethoxy-
benzaldehyde, aniline and trimethyl phosphite under
solvent-free conditions at 100 ℃. Since Al(H2PO4)3 is a
heterogeneous catalyst, it was separated and reused after
being washed with methanol and dried at 100 ℃ for 60
min. The results showed that the catalyst can be used 5
times without significant loss of its activity (Table 2).
Table 2 Investigation on reusability of the catalyst in the reac-
tion of 2,4-dimethoxybenzaldehyde with aniline and trimethyl
phosphite
Compound 16 White solid, m.p. 133—135 ℃. 1H
NMR (CDCl3, 400 MHz) δ: 2.53 (s, 3H), 3.41 (d, J＝
10.5 Hz, 3H), 3.80 (d, J＝10.5 Hz, 3H), 4.60 (br, 1H),
5.06 (d, J＝23.8 Hz, 1H), 6.58 (d, J＝8.5 Hz, 2H), 6.72
(t, J＝7.3 Hz, 1H), 7.10—7.28 (m, 5H), 7.55 (d, J＝2.7
Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ: 19.68, 51.89
(d, J＝151.2 Hz), 53.72 (d, J＝6.9 Hz), 53.85 (d, J＝6.9
HZ), 113.81, 118.69, 126.64 (d, J＝2.9 Hz), 127.21 (d,
J＝4.5 Hz), 128.96, 129.25, 130.65 (d, J＝2.5 Hz),
133.68, 136.33 (d, J＝6.7 Hz), 145.79 (d, J＝14.4 Hz);
31P NMR (CDCl3, 161 MHz) δ: 25.86; IR (KBr) ν: 3314
(NH), 1234 (P＝O), 1060, 1019 (P—O—Me); MS m/z
(%): 305 (M＋, 21), 196 (100), 194 (18), 109 (12), 104
(64), 91 (18), 77 (75). Anal. calcd for C16H20NO3P: C
62.94, H 6.60, N 4.59; found C 62.90, H 6.74, N 4.50.
Run no.
Yielda/%
1
97
96
95
92
90
2
3
4
5
a Yields refer to the pure recovered catalyst.
Conclusion
In conclusion, we have developed an efficient
method for the synthesis of α-amino phosphonate de-
rivatives by an one-pot three-component reaction under
thermal solvent-free conditions. The use of Al(H2PO4)3
as a highly efficient, inexpensive, easy handling,
non-toxic, and reusable catalyst makes the present pro-
cedure eco-friendly and economically acceptable. Fur-
thermore, this method with noteworthy advantages such
as short reaction time, high yields and easy work-up can
Results and discussion
First, benzaldehyde was treated with aniline and
trimethyl phosphite in the presence of Al(H2PO4)3 under
solvent-free conditions at 100 ℃. The reaction pro-
Chin. J. Chem. 2010, 28, 285— 288
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
287

Maghsoodlou et al.
FULL PAPER
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methodologies.
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Acknowledgements
We gratefully acknowledge the funding support re-
ceived for this project from the Research Council of the
University of Sistan and Baluchestan.
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Chin. J. Chem. 2010, 28, 285— 288