Sodium dihydrogen phosphate as an efficient catalyst for one-pot, three-component synthesis of α-aminophosphonates under solvent-free conditions at room temperature

Article abstract of DOI:10.1080/00397910903340728

A simple, efficient, and general method has been developed for the one-pot, three-component synthesis of -aminophosphonates from a condensation reaction of trimethyl phosphite, aldehydes, and amines in the presence of sodium dihydrogen phosphate under solvent-free conditions. Thus, α-aminophosphonates were synthesized relatively quickly in good yields at room temperature.

Full text of DOI:10.1080/00397910903340728

This article was downloaded by: [Princeton University]
On: 21 July 2013, At: 03:36
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
Sodium Dihydrogen Phosphate as
an Efficient Catalyst for One-Pot,
Three-Component Synthesis of α-
Aminophosphonates Under Solvent-Free
Conditions at Room Temperature
Zahed Karimi-Jaberi a , Mohammad Amiri a & Naghmeh Sadeghi a
a Department of Chemistry, Islamic Azad University, Firoozabad
Branch, Firoozabad, Fars, Iran
Published online: 25 Aug 2010.
To cite this article: Zahed Karimi-Jaberi , Mohammad Amiri & Naghmeh Sadeghi (2010) Sodium
Dihydrogen Phosphate as an Efficient Catalyst for One-Pot, Three-Component Synthesis of α-
Aminophosphonates Under Solvent-Free Conditions at Room Temperature, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 40:19, 2948-2953,
DOI: 10.1080/00397910903340728
To link to this article: http://dx.doi.org/10.1080/00397910903340728
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the
“Content”) contained in the publications on our platform. However, Taylor & Francis,
our agents, and our licensors make no representations or warranties whatsoever as to
the accuracy, completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content
should not be relied upon and should be independently verified with primary sources
of information. Taylor and Francis shall not be liable for any losses, actions, claims,
proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or
howsoever caused arising directly or indirectly in connection with, in relation to or arising
out of the use of the Content.

This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &
Conditions of access and use can be found at http://www.tandfonline.com/page/terms-
and-conditions

Synthetic Communications1, 40: 2948–2953, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903340728
SODIUM DIHYDROGEN PHOSPHATE AS AN EFFICIENT
CATALYST FOR ONE-POT, THREE-COMPONENT
SYNTHESIS OF a-AMINOPHOSPHONATES
UNDER SOLVENT-FREE CONDITIONS AT
ROOM TEMPERATURE
Zahed Karimi-Jaberi, Mohammad Amiri, and
Naghmeh Sadeghi
Department of Chemistry, Islamic Azad University, Firoozabad Branch,
Firoozabad, Fars, Iran
A simple, efficient, and general method has been developed for the one-pot, three-component
synthesis of a-aminophosphonates from a condensation reaction of trimethyl phosphite,
aldehydes, and amines in the presence of sodium dihydrogen phosphate under solvent-free
conditions. Thus, a-aminophosphonates were synthesized relatively quickly in good yields
at room temperature.
Keywords: a-Aminophosphonates; room temperature; sodium dihydrogen phosphate; solvent-free;
trimethyl phosphite
a-Aminophosphonates are an important class of compounds because they are
considered as structural analogs of the corresponding a-amino acids. Their
utilities as enzyme inhibitors, antibiotics, and pharmacological agents are well
documented.[1–4] Thus, an efficient synthesis of these compounds has been of great
interest in recent years. A number of the synthetic methods for a-aminophosphonates
have been developed during the past two decades.[5,6] One-pot, three-component con-
densation of aldehydes, amines, and dimethylphosphite or trimethylphosphite is the
most convenient method for the preparation of these compounds. In this context,
some methods and catalysts have been reported such as LiClO4,[7] oxalic acid,[8]
TaCl5–SiO2,[9] b-cyclodextrin,[10] Mg(ClO4)2,[11] Bi(NO3)2,[12] Amberlite-IR 120,[13]
H3PW12O40,[14] ionic liquid,[15,16] classical heating,[17] TiO2,[18] and silica sulfuric
acid.[19] Although these approaches are satisfactory for synthesis of a-aminophospho-
nate, the harsh reaction conditions, expensive reagents, use of toxic organic solvents,
and long reaction times limit the use of these methods.
Because of our interest in the development of practical, safe, and environmen-
tally friendly procedures for several important organic transformations,[20–23] we
Received August 20, 2009.
Address correspondence to Zahed Karimi-Jaberi, Department of Chemistry, Islamic Azad
University, Firoozabad Branch, P.O. Box 74715-117, Firoozabad, Fars, Iran. E-mail: zahed.karimi@
yahoo.com
2948

SYNTHESIS OF a-AMINOPHOSPHONATES
2949
Scheme 1. Synthesis of a-amino phosphonates.
now describe a simple, general, and efficient protocol for the synthesis of
a-aminophosphonates using NaH2PO4 ꢀ H2O under solvent-free conditions at room
temperature.
To optimize the reaction conditions, the reaction of trimethyl phosphite with
imine generated in situ from benzaldehyde and aniline was used as a model reaction.
The optimized reactant ratios were found to be 1.0 equiv. benzaldehyde, 1.0 equiv.
aniline, and 1.0 equiv. trimethylphosphite in the presence of 1.0 equiv. solid NaH2-
PO4 ꢀ H2O. The expected aminophosphonate was produced in 96% yield after 15 min
at room temperature without the use of any solvent (Scheme 1). After completion of
the reaction, the catalyst (NaH2PO4) can easily be separated from the reaction
mixture. To show the generality and scope of the sodium dihydrogen phosphate–
promoted a-aminophosphonate synthesis, the reaction was examined with various
structurally diverse aldehydes, amines, and trimethylphosphite. The results are
summarized in Table 1.
These data clearly show that different aromatic aldehydes were success-
fully converted into the corresponding a-aminophosphonate in excellent yields
Table 1. Synthesis of a-aminophosphonates in the presence of sodium
dihydrogen phosphate
Entry
R
R0
C6H5
Time (min)
Yields (%)
a
b
c
d
e
f
C6H5
4-ClC6H4
15
10
15
10
15
30
75
60
15
10
10
10
10
75
15
25
30
45
50
50
96
94
98
90
89
92
95
86
87
97
88
82
80
84
90
91
75
94
95
93
C6H5
C6H5
4-NO2C6H4
4-MeC6H4
4-HOC6H4
4-CNC6H4
4-MeOC6H4
C6H5
C6H5
C6H5
C6H5
C6H5
g
h
i
4-ClC6H4
4-ClC6H4
4-NO2C6H4
4-BrC6H4
4-ClC6H4
4-MeC6H4
4-NO2C6H4
C6H5
4-HOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeC6H4
2,3-Cl2C6H3
2,4-Cl2C6H3
2,6-Cl2C6H3
j
k
l
m
n
o
p
q
r
C6H5
C6H5
=
C6H5CH CH
C6H5
2-HOC6H4
2-HOC6H4
s
4-MeOC6H4
4-MeC6H4
t

2950
Z. KARIMI-JABERI, M. AMIRI, AND N. SADEGHI
Table 2. Reusability of catalyst for the synthesis of 4a
Experimental trial
Yields (%)a
1
2
3
96
85
81
aAll reactions are carried out under same conditions
as Table 1, entry a.
at room temperature. The presence of electron-withdrawing or electron-
donating substituents on the aromatic ring makes no difference to the course of
the reaction.
This method offers some advantages in term of simplicity of performance,
solvent-free condition, and short reaction time. Several examples illustrating this
novel and general method for the synthesis of a-aminophosphonates 4a–t are sum-
marized in Table 1. All products are known compounds, and their structures were
confirmed by comparison with their known physical and spectral [NMR and
infrared (IR)] data.
Various functionalities present in the aryl aldehydes, such as halogen, methoxy,
hydroxyl, cyano, and nitro groups, were tolerated (see Table 1). Furthermore,
unsaturated aldehydes, such as cinnamaldehydes (entry r), gave the corresponding
phosphonate without any polymerization under these reaction conditions. The reac-
tion can also proceed with several functionalities present in the aromatic amine
such as halogen, hydroxyl, and nitro groups. In all these cases, the corresponding
a-aminophosphonates were obtained in good yields at room temperature without
formation of any side products such as a-hydroxyphosphonate. It is important to
note that the synthesis of a-aminophosphonates could not be achieved in the absence
of catalyst (NaH2PO4).
The catalyst was recovered quantitatively after each experiment and can be
reused without losing its activity. The reusability of the catalyst after three successive
reactions of trimethyl phosphite, benzaldehyde, and aniline is shown in Table 2.
The catalyst was still active when it was used for the third time, but the yield of
the product decreased each time.
The mechanism of this reaction is believed to involve formation of an activated
imine by the acidic catalyst so that addition of the phosphite is facilitated to give a
phosphonium intermediate, which then undergoes reaction with the water generated
during formation of the imine to give the a-aminophosphonate and methanol as
shown in Scheme 2.[16]
In conclusion, we describe a convenient and efficient process for the synthesis
of a-aminophosphonates by one-pot reaction of trimethyl phosphite, aldehydes,
and amines in the presence of sodium dihydrogen phosphate at room temperature
under solvent-free conditions. This method offers some advantages in terms of reu-
sability of catalyst, simplicity of performance, short reaction times, solvent-free
condition, and low cost, and it follows the guidelines of green chemistry. The cata-
lyst is readily available and inexpensive, and it can be handled conveniently and
removed from the reaction mixture. We believe that this is a convenient, economic,

SYNTHESIS OF a-AMINOPHOSPHONATES
2951
Scheme 2. Proposed mechanism.
and user-friendly process for the synthesis of a-aminophosphonates of biological
and medicinal importance.
EXPERIMENTAL
General Procedures for Preparation of a-Aminophosphonates 4a–t
A mixture of aldehyde (1 mmol), amine (1 mmol), trimethyl phosphite
(1 mmol), and NaH2PO4 ꢀ H2O (1 mmol) was stirred at room temperature for the
appropriate time indicated in Table 1. After completion of the reaction, as indicated
by thin-layer chromatography (TLC; ethyl acetate=n-hexane 1=4), chloroform
(10 ml) was added and the catalyst was recovered by filtration. Filtrates were evapo-
rated to remove the solvent. The solid obtained was recrystallized from ethanol to
afford pure products.
Spectral Data for Compound 4a
1
White solid, mp 87 ꢁC; H NMR (500 MHz, CDCl3): d 3.51 (d, J ¼ 10.5 Hz,
3H), 3.81 (d, J ¼ 10.6 Hz, 3H), 4.82 (d, J ¼ 24 Hz, 1H), 6.64 (d, J ¼ 8.0 Hz, 2H),
6.74 (t, J ¼ 7.2 Hz, 1H), 7.10 (t, J ¼ 7.7 Hz, 2H), 7.30 (t, J ¼ 7.5 Hz, 1H), 7.39 (t,
J ¼ 7.4 Hz, 2H), 7.50 (d, J ¼ 7.3 Hz, 2H); 13C NMR (125 MHz, CDCl3): d 54.1 (d,
1
2JP–C ¼ 7.0 Hz, OCH3), 54.2 (2JP–C ¼ 6.8 Hz, OCH3), 56.2 (d, JP–C ¼ 150 Hz, CH),
3
3
114.3 (CH), 119.0 (CH), 128.2 (d, JP–C ¼ 5.8 Hz, CH), 128.4 (d, JP–C ¼ 3.1 Hz,
2
CH), 129.1 (CH), 131.2 (CH), 136.0 (C), 146.6 (d, JP–C ¼ 14.5 Hz, C).
ACKNOWLEDGMENT
We gratefully acknowledge the financial support from the Research Council of
Islamic Azad University of Firoozabad.

2952
Z. KARIMI-JABERI, M. AMIRI, AND N. SADEGHI
REFERENCES
1. Atherton, F. R.; Hassal, C. H.; Lambert, R. W. Synthesis and structure–activity relation-
ships of antibacterial phosphonopeptides incorporating (1-aminoethyl)phosphonic acid
and (aminomethyl)phosphonic acid. J. Med. Chem. 1986, 29, 29–40.
2. Baylis, E. K.; Campbell, C. D.; Dingwall, J. G. 1-Aminoalkylphosphonous acids, part 1:
Isosteres of the protein amino acids. J. Chem. Soc., Perkin Trans. 1 1984, 2845–2853.
3. Kafarski, P.; Lejczak, B. Biological activity of aminophosphonic acids. Phosphorous,
Sulphur, Silicon Relat. Elem. 1991, 63, 193–215.
4. Allen, M. C.; Fuhrer, W.; Tuck, B.; Wade, R.; Wood, J. M. Renin inhibitors: Synthesis of
transition-state analog inhibitors containing phosphorus acid derivatives at the scissile
bond. J. Med. Chem. 1989, 32, 1652–1661.
5. Kukhar, V. P.; Hudson, H. R. Aminophosphonic and Aminophosphinic Acids; John Wiley
& Sons: Chichester, UK, 2000.
6. Engel, R.; Cohen, J. I. Synthesis of Carbon–Phosphorus Bonds, 2nd ed.; CRC Press: Boca
Raton, Fl, 2003.
7. Azizi, N.; Saidi, M. R. Lithium perchlorate–catalyzed three-component coupling: A facile
and general method for the synthesis of a-aminophosphonates under solvent-free
conditions. Eur. J. Org. Chem. 2003, 4630–4633.
8. Vahdat, S. M.; Baharfar, R.; Tajbakhsh, M.; Heydari, A.; Baghbanian, S. M.; Khaksar, S.
Organocatalytic synthesis of a-hydroxy and a-aminophosphonates. Tetrahedron Lett.
2008, 49, 6501–6504.
9. Chandrasekhar, S.; Prakash, S. J.; Jagadeshwar, V.; Narsihmula, C. Three-component
coupling catalyzed by TaCl5–SiO2: Synthesis of a-amino phosphonates. Tetrahedron Lett.
2001, 42, 5561–5563.
10. Kaboudin, B.; Sorbiun, M. b-Cyclodextrin as an efficient catalyst for the one-pot syn-
thesis of 1-aminophosphonic esters in water. Tetrahedron Lett. 2007, 48, 9015–9017.
11. Wu, J.; Sun, W.; Xia, H.-G.; Sun, X. A facile and highly efficient route to a-amino phos-
phonates via three-component reactions catalyzed by Mg(ClO4)2 or molecular iodine.
Org. Biomol. Chem. 2006, 4, 1663–1666.
12. Bhattacharya, A. K.; Kaur, T. An efficient one-pot synthesis of a-amino phosphonates
catalyzed by bismuth nitrate pentahydrate. Synlett 2007, 5, 745–748.
13. Bhattacharya, A. K.; Rana, K. C. Amberlite-IR 120–catalyzed three-component synthesis
of a-amino phosphonates in one pot. Tetrahedron Lett. 2008, 49, 2598–2601.
14. Heydari, A.; Hamadi, H.; Pourayoubi, M. A new one-pot synthesis of a-amino phospho-
nates catalyzed by H3PW12O40. Catal. Commun. 2007, 8, 1224–1226.
15. Akbari, J.; Heydari, A. A sulfonic acid functionalized ionic liquid as a homogeneous and
recyclable catalyst for the one-pot synthesis of a-aminophosphonates. Tetrahedron Lett.
2009, 50, 4236–4238.
16. Lee, S.; Park, J. H.; Lee, J. K.; Kang, J. Lanthanide triflate–catalyzed three-component
synthesis of a-amino phosphonates in ionic liquids: A catalyst reactivity and reusability
study. Chem. Commun. 2001, 1698–1699.
17. Hosseini-Sarvari, M. TiO2 as a new and reusable catalyst for one-pot three-component
syntheses of a-aminophosphonates in solvent-free conditions. Tetrahedron 2008, 64,
5459–5466.
18. Ranu, B. C.; Hajra, A. A simple and green procedure for the synthesis of a-aminopho-
sphonate by a one-pot three-component condensation of carbonyl compound, amine,
and diethyl phosphite without solvent and catalyst. Green Chem. 2002, 4, 551–554.
19. Maghsoodlou, M. T.; Khorassani, S. M. H.; Hazeri, N.; Rostamizadeh, M.; Sajadikhah,
S. S.; Shahkarami, Z.; Maleki, N. An efficient synthesis of a-amino phosphonates using
silica sulfuric acid as a heterogeneous catalyst. Heteroatom Chem. 2009, 20, 316–318.

SYNTHESIS OF a-AMINOPHOSPHONATES
2953
20. Hashemi, M. M.; Ghazanfari, D.; Ahmadibeni, Y.; Karimi-Jaberi, Z.; Ezabadi, A.
Oxidation of aldehydes and ketones into carboxylic acids and esters using 4-amino-2-
chloroperbenzoic acid supported on silica gel. Synth. Commun. 2005, 35, 1103–1107.
21. Hashemi, M. M.; Bakhtiari, M.; Karimi-Jaberi, Z. Efficient solvent-free deprotection of
acetals and trimethylsilyl ethers with iodic acid on silica gel under microwave irradiation.
Russ. J. Org. Chem. 2007, 43, 621–622.
22. Hashemi, M. M.; Rahimi, A.; Karimi-Jaberi, Z. Sodium hypochlorite=montmorillonite
K10: An effective oxidant for the oxidation of thiols to disulfides. Lett. Org. Chem.
2005, 2, 485–486.
23. Karimi-Jaberi, Z.; Hashemi, M. M. One step synthesis of 14-alkyl- or aryl-14H-
dibenzo[a, j]xanthenes using sodium hydrogen sulfate as catalyst. Monatsh. Chem. 2008,
139, 605–608.