One-pot, ahree-component synthesis of α-amino phosphonates using NaHSO4-SiO2 as an efficient and reusable catalyst

Article abstract of DOI:10.1080/00397911.2010.523153

A simple, efficient, and environmentally benign method has been developed for the synthesis of α-amino phosphonates. One-pot, three-component reaction of aldehyds, amines, and trialkylphosphite in the presence of silica-supported sodium hydrogen sulfate (NaHSO₄-SiO₂) as an inexpensive and reusable catalyst under solvent-free conditions at 80 °C affords the corresponding α-amino phosphonates in good yields and short reaction times.

Full text of DOI:10.1080/00397911.2010.523153

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One-Pot, Three-Component Synthesis of
α-Amino Phosphonates Using NaHSO4-
SiO2 as an Efficient and Reusable
Catalyst
Malek Taher Maghsoodlou a , Reza Heydari a , Sayyed Mostafa Habibi-
Khorassani a , Nourallah Hazeri a , Seyed Sajad Sajadikhah a , Mohsen
Rostamizadeh a & Mojtaba Lashkari a
a Department of Chemistry , Faculty of Science, University of Sistan
and Baluchestan , Zahedan , Iran
Accepted author version posted online: 30 Jun 2011.Published
online: 14 Sep 2011.
To cite this article: Malek Taher Maghsoodlou , Reza Heydari , Sayyed Mostafa Habibi-Khorassani ,
Nourallah Hazeri , Seyed Sajad Sajadikhah , Mohsen Rostamizadeh & Mojtaba Lashkari (2012) One-Pot,
Three-Component Synthesis of α-Amino Phosphonates Using NaHSO4-SiO2 as an Efficient and Reusable
Catalyst, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 42:1, 136-143, DOI: 10.1080/00397911.2010.523153
To link to this article: http://dx.doi.org/10.1080/00397911.2010.523153
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Synthetic Communications1, 42: 136–143, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.523153
ONE-POT, THREE-COMPONENT SYNTHESIS OF
a-AMINO PHOSPHONATES USING NaHSO4-SiO2
AS AN EFFICIENT AND REUSABLE CATALYST
Malek Taher Maghsoodlou, Reza Heydari,
Sayyed Mostafa Habibi-Khorassani, Nourallah Hazeri,
Seyed Sajad Sajadikhah, Mohsen Rostamizadeh, and
Mojtaba Lashkari
Department of Chemistry, Faculty of Science, University of Sistan and
Baluchestan, Zahedan, Iran
GRAPHICAL ABSTRACT
Abstract A simple, efficient, and environmentally benign method has been developed for the
synthesis of a-amino phosphonates. One-pot, three-component reaction of aldehyds, amines,
and trialkylphosphite in the presence of silica-supported sodium hydrogen sulfate (NaHSO4-
SiO2) as an inexpensive and reusable catalyst under solvent-free conditions at 80 ꢀC affords
the corresponding a-amino phosphonates in good yields and short reaction times.
Keywords a-Amino phosphonates; heterogeneous catalyst; NaHSO4-SiO2; reusable
catalyst; trialkylphosphite
INTRODUCTION
Organophosphorus compounds have found a wide range of applications in the
areas industrial, agricultural, and medicinal chemistry owing to their biological and
physical properties as well as their utility as synthetic intermediates.[1] In recent years,
a-amino phosphonates have received attention as structural analogs of the corre-
sponding a-amino acids. The activities of a-amino phosphonates as HIV protease,[2]
enzyme inhibitors,[3] antibiotics,[4] peptide mimics,[5] herbicide, insecticides and
fungicides,[6] antitheromboticagents,[7] antimicrobial agents,[8] and inhibitors of
UDP-galactopyranose mutase[9] are reported in the literature.
Received May 26, 2010.
Address correspondence to Malek Taher Maghsoodlou, Department of Chemistry, Faculty of
Science, University of Sistan and Baluchestan, P. O. Box 98135-674, Zahedan, Iran. E-mail:
mt_maghsoodlou@yahoo.com
136

a-AMINO PHOSPHONATES SYNTHESIS
137
Scheme 1. Synthesis of a-amino phosphonates.
Catalytic methods are currently used in synthetic organophosphorus chemistry
to obtain various organophosphorus compounds, in particular, functionalized
phosphonates and phosphinates, which attract special attention because of their
biological activities.[10] A large number of procedures have been developed for the
synthesis of a-amino phosphonates since the first synthesis by Fields.[11] Recently,
one-pot, three-component synthesis starting from aldehydes, amines, and dialkylpho-
sphites or trialkylphosphites has been reported using lanthanide triflate,[12] InCl3,[13]
scandium tris(dodecyl sulfate),[14] lithium perchlorate,[15] CF3CO2H,[16] In(OTf)3,[17]
magnesium perchlorate,[18] PhNMe3Cl,[19] H3PW12O40,[20] Amberlyst-15,[21]
Amberlite-IR 120,[22] sulfamic acid,[23] TiO2,[24] oxalic acid,[25] trifluoroethanol,[26] and
FeCl3 ꢁ tetrahydrofuran (THF).[27] However, many of these methods suffer from some
disadvantages such as long reaction times, environmental pollution caused by utiliza-
tion of organic solvents, poor yields, stoichiometric amounts of catalysts, costly and
moisture-sensitive catalysts, highly toxic catalysts, and drastic reaction conditions.
Therefore, there is a need to develop a facile one-pot synthesis of a-amino phospho-
nates using mild reaction conditions and inexpensive or commercially available
reagents.
Recently, the use of solid acidic catalysts supported on silica has offered impor-
tant advantages in organic synthesis, for example, operational simplicity, environmen-
tal compatibility, lack of toxicity, reusability, low cost, and ease of preparation,
handling, and isolation. Silica-supported sodium hydrogen sulfate (NaHSO4-SiO2)
is well known as an efficient heterogeneous catalyst for many organic trasforma-
tions.[28] This reagent can be prepared from NaHSO4 and silica gel.[28a] However,
solvent-free reactions have received more attention in comparison with their homo-
geneous counterparts because of economical and environmental demands, short reac-
tion times, simple processes, increased product purities and yields, and precise control
of reaction parameters.[29] In the present article, we report a simple and effective
procedure for the one-pot, three-component synthesis of a-amino phosphonates deri-
vatives from reaction of aldehydes, amines, and trialkylphosphite in the presence of
NaHSO4-SiO2 as an inexpensive and reusable catalyst under solvent-free conditions
at 80 ꢀC (Scheme 1).
RESULTS AND DISCUSSION
First, to find out the optimum quantity of silica-supported sodium hydrogen
sulfate, the reaction of benzaldehyde (1 mmol), aniline (1 mmol), and trimethylpho-
sphite (1 mmol) was carried out using different quantities of NaHSO4-SiO2 under
solvent-free conditions at 80 ꢀC (Table 1). As shown in Table 1, the use of 0.05 g

138
M. T. MAGHSOODLOU ET AL.
Table 1. Optimization amount of NaHSO4-SiO2 for the reaction of benzaldehyde,
aniline, and trimethylphosphite under solvent-free conditions at 80 ꢀC
Entry
Catalyst (g)
Time (min)
Yielda (%)
1
2
3
4
5
6
No catalyst
0.01
0.02
24 h
100
80
43
81
89
91
95
94
0.03
0.05
65
45
0.1
30
aYields refer to the pure isolated products.
of catalyst resulted in the greatest yield in 45 min. Poor yield (43%) was obtained
when the reaction was carried out in the absence of NaHSO4-SiO2 at 80 ꢀC under
solvent-free conditions for 24 h.
Thus, several reactions of different aldehydes, amines, and trialkylphosphite
were examined in the presence of NaHSO4-SiO2 (0.05 g) as a catalyst under solvent-
free conditions at 80 ꢀC. The results are summarized in Table 2. In all cases, the
one-pot, three-component reaction proceeded smoothly to afford the corresponding
a-amino phosphonates in good to excellent yields. As shown in Table 2, the reaction
of anilines with a variety of aromatic aldehydes containing electron-deficient and=or
Table 2. Preparation of a-amino phosphonates
Entry
R1
R2
R3
Time (min)
Yielda (%)
Ref.b
1
2
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Et
45
120
20
95
94
94
91
93
93
92
90
94
93
69
91
57
95
96
97
96
96
95
92
93
32
38
33
36
35
36
32
38
35
38
33
39
38
3
4-NO2-C6H4
4-NO2-C6H4
4-NMe2-C6H4
4-F-C6H4
Me
Et
4
60
50
5
Me
Et
6
100
65
7
4-OH-C6H4
4-Me-C6H4
3-Cl-C6H4
Me
Et
8
180
45
9
Me
Et
10
11
12
13
14
15
16
17
18
19
20
21
3-Cl-C6H4
CH3CH2CH2
Ph
110
180
90
Me
Me
Et
PhCH2
4-OMe-C6H4
2,4-di-OMe-C6H3
2,3-di-OMe-C6H3
2,6-di-Cl-C6H3
2,3-di-OMe-C6H3
2,5-di-OMe-C6H3
Ph
CH3CH2CH2
4-OMe-C6H4
2-F-C6H4
180
50
c
Me
Me
Me
Me
Me
Me
Et
—
c
55
35
—
c
4-Br-C6H4
4-Br-C6H4
4-Cl-C6H4
4-Cl-C6H4
3-NO2-C6H4
4-NO2-C6H4
—
c
55
55
—
c
—
50
39
30
32
3-NO2-C6H4
4-NO2-C6H4
120
50
Me
aYields refer to the pure isolated products.
bAll known products have been reported previously in the literature and were characterized by comparison
of IR and NMR spectra with authentic samples.
cThe new compounds synthesized in this work.

a-AMINO PHOSPHONATES SYNTHESIS
139
Table 3. Investigation of reusability of the
catalyst in the reaction of benzaldehyde with
aniline and trimethylphosphite
Run
Yielda (%)
1
2
3
4
5
95
94
91
87
86
aYields refer to the pure recovered catalyst.
electron-releasing groups and trimethyl=triethylphosphite proceeded to afford
a-amino phosphonates in good to excellent yields. On the basis of experimental
results, the rates of all reactions in the presence of triethylphosphite were reduced
in comparison with trimethylphosphite under constant conditions. We have also
prepared five new analogs of these compounds in excellent yields (Table 2, entries
14–18). These new compounds were characterized by elemental analyses, melting
point, infrared (IR), NMR (1H, 13C and 31P), and mass spectroscopies. In addition,
the reaction of benzaldehyde, aniline, and triphenylphosphite was checked in the
presence of NaHSO4-SiO2 under solvent-free conditions at 80 ꢀC for 24 h, but unfor-
tunately the expected corresponding a-amino phosphonate was not obtained.
The feasibility of reusing the catalyst was also examined by treating benzal-
dehyde with aniline and trimethylphosphite in the presence of NaHSO4-SiO2 under
solvent-free conditions at 80 ꢀC. The separated catalyst was reused after being
washed with methanol and dried at 100 ꢀC for 60 min. The results showed that the
catalyst can be used five times without significant loss of its activity (Table 3).
CONCLUSION
In conclusion, silica-supported sodium hydrogen sulfate was found to be an
efficient, commercially available, environmentally friendly, and reusable catalyst
for the one-pot, three-component reaction of aldehydes, amines, and trialkylpho-
sphite to afford a-amino phosphonates in good to excellent yields. The reactions were
carried out under thermal solvent-free conditions with short reaction times. The ther-
mal solvent-free green procedure offer advantages including shorter reaction times,
environmentally friendliness, simple workup, good yields, and cost-effective recovery
and reusability of catalyst for a few times without significant loss of its activity.
EXPERIMENTAL
Melting points and IR spectra of all compounds were measured on an Electro-
1
thermal 9100 apparatus and a Shimadzu IR-460 spectrometer respectively. The H,
13C, and 31P NMR spectra were obtained on Bruker DRX-250 and 400 Avance
instruments with CDCl3 as a solvent. Elemental analyses were performed using a
Heraeus CHN-O-Rapid analyzer. Mass spectra were recorded on an Agilent
Technology (HP) spectrometer operating at an ionization potential of 70 eV. All

140
M. T. MAGHSOODLOU ET AL.
reagents and solvents obtained from Fluka and Merck were used without further
purification.
General Procedure for the Synthesis of a-Amino Phosphonates
The mixture of aldehyde (1 mmol), amine (1 mmol), and NaHSO4-SiO2 (0.05 g)
were stirred for a few minutes. Then trimethyl=triethylphosphite (1 mmol) was
added, and the mixture was stirred at 80 ꢀC in oil bath for the appropriate time
(see Table 2). After completion of the reaction (monitored by thin-layer chromato-
graohy, 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 ꢂ 3). The organic layer was dried over anhydrous Na2SO4 and evaporated.
The crude product was purified by silica-gel column chromatography with the
mixture of n-hexane=EtOAc (7:3) as eluant to provide pure a-amino phosphonates.
Spectral data for new products are given.
Selected Data
1
Compound 14 (Table 2, Entry 14). Yellow solid, mp 131–133 ꢀC. H NMR
3
(CDCl3, 250 MHz) d: 3.45 (3H, d, JPH ¼ 10.5 Hz, P-OCH3), 3.67 (3H, s, OCH3),
3
3.75 (3H, s, OCH3), 3.80 (3H, d, JPH ¼ 10.7 Hz, P-OCH3), 3.89 (3H, s, OCH3),
2
4.18 (1H, br, NH), 5.25 (1H, d, JPH ¼ 24.0 Hz, CHP), 6.44–6.70 (6H, m, Ar),
1
7.34–7.38 (1H, m, Ar); 13C NMR (CDCl3, 62.9 MHz) d: 48.12 (d, JPC ¼ 157.3 Hz),
2
2
53.68 (d, JPC ¼ 6.9 Hz), 53.84 (d, JPC ¼ 6.9 Hz), 55.27, 55.61, 55.79, 98.52, 104.90
(d, J ¼ 2.5 Hz), 114.67, 115.05, 116.40, 128.97 (d, J ¼ 5.0 Hz), 140.02 (d, J ¼ 15.7 Hz),
152.61, 158.18 (d, J ¼ 6.9 Hz), 160.51; 31P NMR (CDCl3, 101 MHz) d: 26.41; IR
(KBr) t: 3320 (NH), 1235 (P¼O), 1060, 1039 (P–OꢃMe); MS m=z (%): 381 (Mþ,
14), 272 (100), 259 (10), 257 (11), 149 (88), 123 (53), 121 (69), 109 (6), 92 (10), 79
(18), 77 (17). Anal. calcd. for C18H24NO6P: C, 56.69; H, 6.34; N, 3.67. Found: C,
56.83; H, 6.49; N, 3.75.
1
Compound 15 (Table 2, Entry 15). White solid, mp 84–85 ꢀC. H NMR
3
3
(CDCl3, 250 MHz) d: 3.54 (3H, d, JPH ¼ 10.5 Hz, P-OCH3), 3.83 (3H, d, JPH
¼
10.3 Hz, P-OCH3), 3.85 (3H, s, OCH3), 3.98 (3H, s, OCH3), 4.63 (1H, br, NH),
5.43 (1H, d, JPH ¼ 24.0 Hz, CHP), 6.56–7.11 (7H, m, Ar); 13C NMR (CDCl3,
2
2
2
2
62.9 MHz) d: 47.74 (d, JPC ¼ 157.4 Hz), 53.68 (d, JPC ¼ 6.9 Hz), 53.90 (d, JPC
¼
6.9 Hz), 55.65, 60.94, 112.16 (d, J ¼ 2.5 Hz), 113.34 (d, J ¼ 2.8 Hz), 114.54 (d,
J ¼ 18.5 Hz), 118.02 (d, J ¼ 7.0 Hz), 119.70 (d, J ¼ 4.0 Hz), 124.31 (d, J ¼ 2.6 Hz),
124.53 (d, J ¼ 3.5 Hz), 129.27, 134.42 (dd, J ¼ 14.7 Hz, J ¼ 11.4 Hz), 147.03 (d,
J ¼ 7.4 Hz), 151.90 (d, JFC ¼ 237.8 Hz), 152.33 (d, J ¼ 1.7 Hz); 31P NMR (CDCl3,
1
101 MHz) d: 25.17; 19F NMR (CDCl3, 376.5 MHz) d: ꢃ135.22; IR (KBr) t: 3316
(NH), 1240 (P¼O), 1052, 1030 (PꢃOꢃMe); MS m=z (%): 369 (Mþ, 6), 260 (100),
245 (10), 135 (16), 123 (13), 122 (11), 111 (21), 109 (10), 95 (8), 79 (10). Anal. calcd.
for C17H21FNO5P: C, 55.29; H, 5.73; N, 3.79. Found: C, 55.41; H, 5.70; N, 3.76.
1
Compound 16 (Table 2, Entry 16). White solid, mp 94–96 ꢀC. H NMR
(250 MHz, CDCl3) d: 3.62 (3H, d, 3JPH ¼ 10.8 Hz, P-OCH3), 3.86 (3H, d, 3JPH ¼ 10.9 Hz,
P-OCH3), 4.62 (1H, br, NH), 5.80 (1H, d, 2JPH ¼ 28.8 Hz, CHP), 6.49–6.54 (2H, m, Ar),

a-AMINO PHOSPHONATES SYNTHESIS
141
7.14–7.37 (5H, m, Ar); 13C NMR (CDCl3, 62.9 MHz) d: 52.74 (d, 1JPC ¼ 157.9 Hz), 53.63
(d, 2JPC ¼ 6.9 Hz), 53.93 (d, 2JPC ¼ 7.5 Hz), 110.79, 115.26, 128.55 (d, J¼ 1.3 Hz), 129.66
(d, J¼ 3.1 Hz), 130.58 (d, J¼ 2.5 Hz), 130.68, 132.06, 134.75 (d, J¼ 5.0 Hz), 136.66 (d,
J¼ 6.9 Hz), 144.57 (d, J¼ 15.7 Hz); 31P NMR (CDCl3, 101 MHz) d: 22.54; IR (KBr)
t: 3324 (NH), 1255 (P¼O), 1061, 1017 (PꢃOꢃMe); MS m=z (%): 443 (Mþ þ 4, 5), 441
(Mþ þ 2, 12), 439 (Mþ, 8), 332 (80), 330 (100), 328 (86), 294 (9), 249 (8), 184 (14), 157
(13), 155 (13), 109 (6), 76 (18). Anal. calcd. for C15H15BrCl2NO3P: C, 41.03; H, 3.44;
N, 3.19. Found: C, 41.20; H, 3.49; N, 3.28.
1
Compound 17 (Table 2, Entry 17). White solid, mp 136–137 ꢀC. H NMR
3
3
(250 MHz, CDCl3) d: 3.48 (3H, d, JPH ¼ 10.5 Hz, P-OCH3), 3.82 (3H, d, JPH
¼
10.7 Hz, P-OCH3), 3.86 (3H, s, OCH3), 3.96 (3H, s, OCH3), 4.26 (1H, br, NH),
2
5.35 (1H, d, JPH ¼ 24.0 Hz, CHP), 6.54 (2H, d, J ¼ 8.8 Hz, Ar), 6.82–7.08 (3H, m,
Ar), 7.17 (2H, d, J ¼ 8.8 Hz); 13C NMR (CDCl3, 62.9 MHz) d: 48.06 (d, JPC
¼
1
2
2
156.6 Hz), 53.80 (d, JPC ¼ 6.9 Hz), 53.85 (d, JPC ¼ 6.9 Hz), 55.67, 60.94, 110.40,
112.18 (d, J ¼ 2.5 Hz), 115.48, 119.64 (d, J ¼ 4.4 Hz), 124.34 (d, J ¼ 2.5 Hz), 129.00,
131.92, 144.88 (d, J ¼ 15.1 Hz), 146.95, 152.33; 31P NMR (CDCl3, 101 MHz) d:
25.42; IR (KBr) t: 3317 (NH), 1267 (P¼O), 1054, 1018 (PꢃOꢃMe); MS m=z (%):
431 (M þ 2, 6), 429 (Mþ, 7), 322 (100), 320 (89), 241 (6), 154 (8), 135 (13), 121 (9),
109 (9), 91 (6), 79 (8). Anal. calcd. for C17H21BrNO5P: C, 47.46; H, 4.92; N 3.26.
Found: C, 47.41; H, 4.97; N, 3.24.
Compound 18 (Table 2, Entry 18). Brownish solid, mp 112–114 ꢀC. 1H
3
NMR (250 MHz, CDCl3) d: 3.46 (3H, d, JPH ¼ 10.5 Hz, P-OCH3), 3.70 (3H, s,
3
OCH3), 3.80 (3H, d, JPH ¼ 10.6 Hz, P-OCH3), 3.88 (3H, s, OCH3), 4.25 (1H, br,
NH), 5.32 (1H, d, 2JPH ¼ 24.8 Hz, CHP), 6.51–7.04 (7H, m, Ar); 13C NMR (CDCl3,
2
2
2
62.9 MHz) d: 47.93 (d, JPC ¼ 155.4 Hz), 53.70 (d, JPC ¼ 6.9 Hz), 53.87 (d, JPC
¼
6.9 Hz), 55.63, 56.37, 111.78, 113.96, 114.79, 123.04, 124.74, 128.99, 144.59 (d,
J ¼ 15.1 Hz), 151.44; 31P NMR (CDCl3, 101 MHz) d: 25.47; IR (KBr) t: 3310
(NH), 1252 (P¼O), 1040, 1024 (PꢃOꢃMe); MS m=z (%): 385 (Mþ, 9), 276 (100),
261 (37), 246 (30), 149 (21), 140 (18), 111 (16), 109 (8), 79 (11). Anal. calcd. for
C17H21ClNO5P: C, 52.93; H, 5.49; N, 3.63. Found: C, 53.04; H, 5.45; N, 3.71.
ACKNOWLEDGMENT
We gratefully acknowledge financial support from the Research Council of the
University of Sistan and Baluchestan.
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