Nano ceria catalyzed synthesis of α-aminophosphonates under ultrasonication

Article abstract of DOI:10.1016/j.tetlet.2011.04.112

A simple, efficient and general method has been developed for the one-pot three component syntheses of α-aminophosphonates. The condensation of aldehyde, amine and triethyl phosphite by employing CeO₂ nanoparticles as catalyst gave α-aminophosphonates. The catalyst showed good recyclability. Nano CeO₂ has been found to be an excellent catalyst for the green synthesis of α-aminophosphonates under ultrasound irradiation and solvent-free condition. The α-aminophosphonates are obtained in good to excellent yield. This catalyst provides cleaner conversion, short reaction time and high selectivity which makes the protocol feasible and economical attractive.

Full text of DOI:10.1016/j.tetlet.2011.04.112

Tetrahedron Letters 52 (2011) 3499–3504
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Nano ceria catalyzed synthesis of
a-aminophosphonates under ultrasonication
⇑
Sandeep M. Agawane, Jayashree M. Nagarkar
Department of Chemistry, Institute of Chemical Technology, Nathalal Parekh Marg, Matunga, Mumbai 400 019, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple, efficient and general method has been developed for the one-pot three component syntheses of
Received 24 February 2011
Revised 28 April 2011
Accepted 29 April 2011
Available online 6 May 2011
a
-aminophosphonates. The condensation of aldehyde, amine and triethyl phosphite by employing CeO2
nanoparticles as catalyst gave -aminophosphonates. The catalyst showed good recyclability. Nano CeO2
has been found to be an excellent catalyst for the green synthesis of -aminophosphonates under ultra-
sound irradiation and solvent-free condition. The -aminophosphonates are obtained in good to excellent
a
a
a
yield. This catalyst provides cleaner conversion, short reaction time and high selectivity which makes the
protocol feasible and economical attractive.
Keywords:
Nano ceria
Kabachnik–Fields reaction
Ultrasound
Ó 2011 Elsevier Ltd. All rights reserved.
Solvent-free
Phosphonic acids and their phosphonate derivatives are of
immense interest in synthetic organic chemistry due to their bio-
reaction times, low yields of the products requiring stoichiometric
amounts of catalysts, excess amounts of phosphorus compounds or
use of additives.
Such reactions under solvent-free condition have received more
attention in comparison with their homogeneous counterparts,
due to economical and environmental demands. There is also a
logical activities.1
a
-Aminophosphonates have been the focus of
attention in recent years because of their structural analogy to
the corresponding -amino acids as well as heterocyclic phospho-
a
nates. These molecules have found a wide range of applications in
the areas of industrial, biological, and medicinal chemistry, as
inhibitors of synthase, HIV protease,2a antibiotics, enzyme inhibi-
tors,2b anti-thrombotic agents,2c herbicides,2d fungicides,2e insecti-
cides,2f plant growth regulators2g,h and as substrates in the
synthesis of phosphonopeptides.2i,j Recently, three-component
synthesis starting from aldehyde, amine and diethylphosphite or
triethylphosphite has been reported by using Lewis acid such as ti-
n(IV) chloride,3a zirconium(IV) chloride3b and boron trifluoride–
diethyl ether complex.3c In addition, these reactions cannot be
carried out in one step with a carbonyl compound, an amine and
a trialkyl phosphite because the amine and water present during
imine formation can decompose or deactivate the Lewis acid.4 This
need to develop a simple process for one-pot synthesis of
ophosphonate using water-tolerant catalysts.
a-amin-
The use of acidic catalysts has attracted considerable attention.6
Amberlyst-15,7a CdI2 and BF3ÁOEt2 have been used as catalyst
7b
7c
by various researchers for the synthesis of a-aminophosphonates.
Sara Sobhani has for the first time reported sodium dodecyl sulfate
(SDS) miceller medium for Kabacknik–Fields reaction.8 Srikant
Bhagat and Asit K. Chakraborti have screened various perchlorates
and also used various zirconium precursors for synthesis of
a
-aminophosphonates.5b,9 Yuan, C have reported a convenient
N-tert-butylsulfinimine-mediated asymmetric synthesis of chiral
a-aminophosphonates at room temperature using potassium car-
drawback has been overcome by some recent methods using
bonate as a base which gave reasonable chemical and enantiomeric
5a
H3PW12O40
,
magnesium perchlorate,5b trimethylanilinium chlo-
yields.10a,b
ride,5c bismuth nitrate pentahydrate,5d scandium tris(dodecyl)
sulfate,5e,f indium(III) chloride,5g samarium(II) iodide,5h metal tri-
flates5i [M(OTf)n, M = La, Li, Mg, Al, Cu, Ce], lithium perchlorate,5j,k
tantalum(V) chloride–silicon dioxide,5l alumina,5m trifluoroacetic
acid,5n montmorillonite KSF,5o stannous chloride5p and (bromodi-
methyl) sulfonium bromide.5q Although these approaches are sat-
Ultrasound assisted synthesis of nanocrystalline material is a
well accepted protocol. It has been demonstrated as an alternative
energy source for organic reactions ordinarily accomplished by
heating. Metal oxide and colloidal metal nanoparticles have re-
ceived considerable attention as catalyst in organic synthesis due
to their high catalytic activity, environmental compatibility, ease
of handling, nontoxic nature and reusability.11 The solvent-less
protocol has an added advantage in the green context.
isfactory for a one-pot synthesis of
a-aminophosphonates, they
suffer from at least one of the following drawbacks such as long
The catalytic activity of ceria is well known for CO2 fixation
and transalkylation.12 Herein we report the nano CeO2 as an
efficient, environmentally benign and high yielding catalyst for
⇑
Corresponding author. Tel.: +91 22 33611111x2222; fax: +91 22 33611020.
E-mail addresses: smagawane@gmail.com (S.M. Agawane), jm.nagarkar@
the synthesis of
a-aminophosphonates under ultrasonication and
ictmumbai.edu.in, jayashreenagarkar@yahoo.co.in (J.M. Nagarkar).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.04.112

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S. M. Agawane, J. M. Nagarkar / Tetrahedron Letters 52 (2011) 3499–3504
Figure 1. A-XRD, B-TEM, C-SEM and D-EDAX spectra of nano CeO2 powder.
O
EtO
OEt
NH2
CHO
P
OEt
Metal Oxide
))))
N
H
+
+
P
EtO
OEt
1 mmol
1 mmol
1 mmol
3
1
2
Scheme 1. Synthesis of
a-aminophosphonate catalyzed by different metal oxides.
H
H
H
O
N
Table 1
Influence of the various metal oxides on the synthesis of
a
-aminophosphonatea
N
H
Sr. no.
Metal oxides
Surface area
Particle size
Yieldb (%)
+
- H2O
1
2
3
4
5
6
7
TiO2
SiO2
ZnO
Al2O3
MgO
14.68 m2/g
—
—
80
67
72
61
66
60
99
P(OEt)
3
60–120 mesh
—
150–300 mesh
—
12.16 m2/g
—
H2O
ꢀ130 m2/g
11 m2/g
214 m2/gc
CeO2
CeO2 (nano)
—
- OH
4–5 nm
Et
EtOH
Et
O
(O)P(OEt)
a
2
Reaction condition: benzaldehyde (1 mmol), aniline (1 mmol), triethyl phos-
phite (1 mmol) and 10 mol % catalyst under ultrasonication for 5 min.
O
O
+
Et
P
b
CH
N
Isolated yield.
Calculated by formula.
CH
C
N
H
H
solvent-free condition. The CeO2 catalyst is prepared by CTAB as-
sisted method,13 which is further modified by using ultrasonica-
tion.18 The size of the prepared catalyst is found to be 4–5 nm
and surface area about 214 m2/g calculated by following formula
Scheme 2. Mechanism of synthesis of a-aminophosphonate catalyzed by CeO2.
where
age crystalline size.14
SL = 6 L.
q
is density (7.134 g/cm3) and L is the XRD determined aver-
Table 1 gives the details about the surface area, particle size and
catalytic activity of TiO2, SiO2, Al2O3, ZnO, MgO, CeO2 and nano
CeO2. CeO2 has both Lewis and Bronsted basic sites15 which are
strong and widely distributed over the CeO2 surface.12b In addition
to this it has smaller particle size and hence has high surface area
due to which nano CeO2 shows better catalytic activity for the syn-
q
Figure 1 shows the XRD, TEM, SEM and EDAX spectra of pre-
pared CeO2. The catalyst was found to be highly active and selec-
tive, affording excellent yield with a high selectivity in a short
reaction time.
Model reaction was carried out by taking the mixture of benz-
aldehyde, aniline, triethyl phosphite and the catalyst (Scheme 1).
thesis of
a-aminophosphonate. The mechanism of this reaction is
well known and involves formation of an activated ‘imine’.16 These
basic sites on CeO2 activate the imine formation due to which

S. M. Agawane, J. M. Nagarkar / Tetrahedron Letters 52 (2011) 3499–3504
3501
addition of phosphite is facilitated to give a phosphonium interme-
diate. This phosphonium intermediate undergoes reaction with
Table 2
water to give the
Scheme 2.
a-aminophosphonate and ethanol as shown in
Influence of the solvent on the synthesis of
a
-aminophosphonatea
Sr. no.
Solvent
Yieldb (%)
Various reaction parameters are optimized for this reaction. The
reaction was carried out with and without solvents keeping the
catalyst amount constant. The various solvents screened were
water, ethanol, toluene, dichloromethane and acetonitrile. It is ob-
served that solvent-free condition gave the excellent yield of prod-
uct than that in the presence of solvents. Table 2 shows the effect
of various solvents on the reaction. Results summarized in Table 3
show the influence of catalyst concentration on the reaction.
5 mol % of catalyst gave maximum yield whereas 2 and 4 mol %
of catalyst gave lower yields.
1
2
3
4
5
6
Water
Ethanol
Toluene
70
72
52
71
97
99
Dichloromethane
Acetonitrile
No solvent
a
Reaction condition: benzaldehyde (1 mmol), aniline (1 mmol), triethyl phos-
phite (1 mmol) and 10 mol % CeO2 under ultrasonication for 5 min.
b
Isolated yield.
Various aromatic and heteroaromatic aldehyde containing elec-
tron donating or electron withdrawing functional groups are trea-
ted with various aliphatic, aromatic and heteroaromatic amines
and did not show any remarkable difference in the yield of desired
products.19 The results are given in Table 4 which shows that all
Table 3
Influence of the catalyst loading on the synthesis of
a
-aminophosphonatea
Yieldb (%)
Sr. no.
Catalyst (mol %)
reactions proceeded cleanly to give the corresponding
a-amin-
1
2
3
4
5
6
7
10
8
6
5
4
99
99
99
99
90
74
30
ophosphonate. Amine substituted with electron withdrawing
group required less time than the amine substituted with electron
donating group (Table 4, entries 3c–g). Similar observation is no-
ticed in case of aromatic aldehyde when they are attached with
electron withdrawing and electron donating groups (Table 4, en-
tries 3j–n). The furfural and 3-amino pyridine (Table 4, entry 3p)
gave less yield and required more time, probably due to the low
reactivity of heterocyclic aldehydes.
2
0
a
Reaction condition: benzaldehyde (1 mmol), aniline (1 mmol) and triethyl
phosphite (1 mmol) for 5 min under solvent-free ultrasonication.
b
Isolated yield.
Table 4
CeO2 catalyzed synthesis of
a
-aminophosphonatesa
Sr. no.
Aldehyde
Amine
Product
Time (min)
Yieldb (%)
CHO
NH2
H
N
3a
5
99
(O)P(OEt)2
CHO
CHO
NH2
NH2
H
N
3bc
30
10
60
97
(O)P(OEt)2
H
N
3c
(O)P(OEt)
2
CH3
NH2
CHO
CHO
H
N
3d
3e
10
10
90
OMe
(O)P(OEt)2
OCH3
NH2
H
N
90
OH
(O)P(OEt)
2
OH
(continued on next page)

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S. M. Agawane, J. M. Nagarkar / Tetrahedron Letters 52 (2011) 3499–3504
Table 4 (continued)
Sr. no.
Aldehyde
Amine
Product
Time (min)
Yieldb (%)
CHO
NH2
H
N
3f
30
87
NO2
(O)P(OEt)
2
NO2
NH2
CHO
H
N
3g
10
92
Cl
(O)P(OEt)
2
Cl
CHO
CHO
CHO
NH2
H
N
3h
3i
20
30
93
85
(O)P(OEt)
2
2
NH2
H
N
N
N
(O)P(OEt)
NH2
Cl
H
N
3j
3k
3l
15
15
20
94
84
95
(O)P(OEt)
2
Cl
CHO
HO
NH2
NH2
NH2
H
N
(O)P(OEt)
2
OH
CHO
O2N
H
N
(O)P(OEt)
2
NO2
CHO
H
N
3m
10
15
87
91
(O)P(OEt)
2
CH3
CHO
NH2
NH2
MeO
H
N
3n
3o
(O)P(OEt)
2
OCH3
O
H
N
CHO
CHO
O
O
20
40
85
76
(O)P(OEt)
N
N
2
NH2
H
N
3p
O
N
(O)P(OEt)
2
a
Reaction condition: aldehyde (1 mmol), amine (1 mmol), triethyl phosphite (1 mmol) and 5 mol % CeO2 under solvent-free ultrasonication.
Isolated yield.
Under stirring.
b
c
Diethyl amine (Table 5) did not react with benzaldehyde to
form the imine, instead -hydroxyphosphonate was obtained
which was analyzed by GCMS. It is due to the base catalyzed addi-
tion of triethyl phosphite to benzaldehyde.17
a

S. M. Agawane, J. M. Nagarkar / Tetrahedron Letters 52 (2011) 3499–3504
3503
Table 5
CeO2 catalyzed synthesis of
a
-hydroxyphosphonatea
Sr. no.
Aldehyde
Amine
Product
Time (min)
20
Yieldb (%)
CHO
OH
P(OEt)2
H
N
3q
99
C2H5
C2H5
O
a
Reaction condition: benzaldehyde (1 mmol), diethylamine (1 mmol), triethyl phosphite (1 mmol) and 5 mol % CeO2 under solvent-free ultrasonication.
Isolated yield.
b
3. (a) Laschat, S.; Kunz, H. Synthesis 1992, 1/2, 90–95; (b) Yadav, J. S.; Reddy, B. V.
S.; Raj, S.; Reddy, K. B.; Prasad, A. R. Synthesis 2001, 15, 2277–2280; (c) Ha, H. J.;
Nam, G. S. Synth. Commun. 1992, 22, 1143–1148.
Table 6
Recyclability of nano CeO2
a
Run
Fresh
99
Run 1
98
Run 2
98
Run 3
97.5
4. Yokomatsu, T.; Yoshida, Y.; Shibuya, S. J. Org. Chem. 1994, 59, 7930–7933.
5. (a) Heydari, A.; Hamadi, H.; Pourayoubi, M. Catal. Commun. 2007, 8, 1224–
1226; (b) Bhagat, S.; Chakraborti, A. K. J. Org. Chem. 2007, 72, 1263–1270; (c)
Heydari, A.; Arefi, A. Catal. Commun. 2007, 8, 1023–1026; (d) Bhattacharya, A.
K.; Kaur, T. Synlett 2007, 745–748; (e) Manabe, K.; Kobayashi, S. Chem. Commun.
2000, 8, 669–670; (f) Qian, C.; Huang, T. J. Org. Chem. 1998, 63, 4125–4128; (g)
Ranu, B. C.; Hajra, A.; Jana, J. Org. Lett. 1999, 1, 1141–1143; (h) Xu, F.; Luo, Y.;
Deng, M.; Shen, Q. Eur. J. Org. Chem. 2003, 24, 4728–4730; (i) Firouzabadi, H.;
Iranpoor, N.; Sobhani, S. Synthesis 2004, 16, 2692–2696; (j) Azizi, N.; Saidi, M. R.
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Kaboudin, B.; Nazari, R. Tetrahedron Lett. 2001, 42, 8211–8213; (n) Akiyama, T.;
Sanada, M.; Fuchibe, K. Synlett 2003, 1463–1464; (o) Yadav, J. S.; Reddy, B. V. S.;
Madan, C. Synlett 2001, 1131–1133; (p) Gallardo-Macias, R.; Nakayama, K.
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Yieldb (%)
a
Reaction condition: benzaldehyde (1 mmol), aniline (1 mmol), triethyl phos-
phite (1 mmol) and 5 mol % recycled CeO2 under ultrasonication for 5 min.
b
Isolated yield.
The aromatic amine and benzaldehyde form imine, and is the
key intermediate in the product-forming pathway.5p This proves
that the formation of a-aminophosphonate can be achieved by cat-
alytic quantity of CeO2 avoiding the use of Lewis acid reagents like
AlCl3, ZrCl4, InCl3, metal triflates, etc. The reaction conditions are
mild and no undesired product formation is seen.
The catalyst was removed from the reaction mixture by centri-
fugation, washed with dichloromethane and dried. Table 6 indi-
cates the reusability of the catalyst. It clearly reveals that the
catalyst can be used for three cycles without much loss in the yield
of desired product.
6. Ko, S.; Yao, C. F. Tetrahedron Lett. 2006, 47, 8827–8829.
7. (a) Tajbakhsh, A.; Heydari, A.; Alinezhad, H.; Ghanei, M.; Khaksarb, S. Synthesis
2008, 3, 352–354; (b) Kabachnik, M. M.; Minaeva, L. I.; Beletskaya, I. P. Synthesis
2009, 14, 2357–2360; (c) Odinets, I. L.; Artyushin, O. I.; Shevchenko, N.;
Petrovskii, P. V.; Nenajdenko, V. G.; Roschenthaler, G. V. Synthesis 2009, 4, 577–
582.
8. Sobhani, S.; Vafaee, A. Synthesis 2009, 11, 1909–1915.
In conclusion, we report the ‘Green Methodology’ for the syn-
9. Bhagat, S.; Chakraborti, A. K. J. Org. Chem. 2008, 73, 6029–6032.
10. (a) Chen, Q.; Yuan, C. Synthesis 2007, 24, 3779–3786; (b) Chen, Q.; Li, J.; Yuan, C.
Synthesis 2008, 18, 2986–2990.
thesis of
ultrasound and solvent-free condition. Secondary amine did not re-
act with benzaldehyde instead gives -hydroxyphosphonate. The
reaction is applicable to aromatic/heteroaromatic aldehydes and
amines. Short reaction time achieved by ultrasonication is the
added advantage of this reaction. The present study can be consid-
a-aminophosphonates using ceria nanoparticles, under
11. (a) Thathagar, M. B.; Beckers, J.; Rothenberg, G. J. Am. Chem. Soc. 2002, 124,
11858–11859; (b) Reetz, M. T.; Westermann, E. Angew. Chem., Int. Ed. 2000, 39,
165–168; (c) Zhao, M.; Crooks, R. M. Angew. Chem., Int. Ed. 1999, 38, 364–366;
(d) Thathagar, M. B.; Beckers, J.; Rothenberg, G. Green Chem. 2004, 6, 215–218.
12. (a) Juarez, R.; Concepcion, P.; Corma, A.; Garcia, H. Chem. Commun. 2010, 46,
4181–4183; (b) Bhanage, B. M.; Fujita, S.; Ikushima, Y.; Arai, M. Appl. Catal., A
2001, 219, 259–266; (c) Juarez, R.; Corma, A.; Garcia, H. Green Chem. 2009, 11,
949–952.
a
ered as the green protocol for synthesis of a-aminophosphonates,
having advantages like solvent-free condition, high yields of de-
sired products, recyclability of the catalyst, good selectivity and
hence environmentally benign methodology.
13. Terribile, D.; Trovarelli, A.; Llorca, J.; Leitenburg, C.; Dolcetti, G. J. Catal. 1998,
178, 299–308.
14. (a) Gregg, S. J.; Rauquerol, J.; Sing, K. S. W. Adsorption at a gas–solid and liquid–
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15. Trovarelli, A. In Catalysis by Ceria and Related Materials; Imperial College Press,
2002; 2, p 409. catalytic science series.
Acknowledgment
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Jaberi, Z.; Amiri, M. Heteroat. Chem. 2010, 21, 96–98.
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The authors are thankful to UGC-Green Technology Centre, New
Delhi, India for awarding the fellowship.
18. General procedure for synthesis of nano ceria: CeO2 nanoparticles were prepared
by adding ammonia solution to an aqueous solution of cerium(III) nitrate in
presence of CTAB. In a typical procedure, added 1 g of Ce(NO3)3 in solution of
CTAB dissolved in 100 cm3 of water. Mole ratio of Ce/CTAB was kept at unity.
pH of the solution was adjusted between 10 and 11 by adding 25% ammonia
solution under vigorous stirring for 2–3 h. The resulting mixture was
ultrasonicated for 10 min and then filtered off. The obtained precipitate was
washed with water and subsequently with acetone and dried at 120 °C for
12 h. It was then calcined at 500 °C for 3 h. The prepared CeO2 was
characterized with various techniques such as X-ray diffractograms (XRD),
Fourier Transform Infra-Red Spectroscopy (FT-IR), Transmission Electron
Microscope (TEM), Field Emission Gun-Scanning Electron Microscopes (FEG–
SEM) coupled with EDAX and X-ray photoelectron spectroscopy (XPS). See
Supplementary data.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.04.112.
References and notes
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(e) Meyer, J. H.; Barlett, P. A. J. Am. Chem. Soc. 1998, 120, 4600–4609; (f) Maier,
L. Phosphorus, Sulfur Silicon Relat. Elem. 1990, 53, 43–67; (g) Maier, L.; Spoerri, H.
Phosphorus, Sulfur Silicon Relat. Elem. 1991, 61, 69–75; (h) Emsley, J.; Hall, D.
Chemistry of Phosphorus; Harper & Row: London, 1976. pp 494; (i) Maier, L.; Lea,
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19. General procedure for synthesis of a-aminophosphonates: In
a 10 ml round
bottom flask taken a mixture of aldehyde (1 mmol) and amine (1 mmol) at
room temperature and then triethyl phosphite (1 mmol) was added. Further
5 mol %, 8.525 mg CeO2 is added to the reaction mixture. Then reaction
mixture was subjected to the ultrasonication for appropriate time. After
completion of the reaction, as indicated by TLC, catalyst was separated by
centrifugation and subsequent washing with dichloromethane. The reaction
mixture diluted with water and product was extracted with dichoromethane

3504
S. M. Agawane, J. M. Nagarkar / Tetrahedron Letters 52 (2011) 3499–3504
(2 Â 10 ml). The organic layer was dried over anhydrous sodium sulphate and
C6H5), 7.51 (d, 2H, C6H5) ppm; GC–MS (EI, 70 eV): m/z (%) = 45(33%), 77(27%),
104(18%), 182(100%) [M]+, 319(3%); IR (KBr) cmÀ1: 3295 (–NH), 2931 (–CH),
1233 (P–O), 1103–997 (P–O–Et). Compound 3i: GC–MS (EI, 70 eV): m/z
(%) = 45(4%), 78(21%), 183(100%), [M]+ 320(3%). Compound 3p: GC–MS (EI,
70 eV): m/z (%) = 173(100%), [M]+ 310 (5%).
evapored under reduce pressure to afford the pure products. Compound 3a:
white solid, mp 97 °C; 1H NMR (300 MHz,CDCl3): d 1.125 (t, 3H, OCH2CH3),
1.298 (t, 3H, OCH2CH3), 3.62–3.75 (m, 1H, OCH2CH3), 3.89–3.99 (m, 1H,
OCH2CH3), 4.07–4.21 (m, 2H, OCH2CH3), 4.84–4.93 (d, 1H, CH), 4.768 (s, 1H,
NH), 6.62 (d, 2H, C6H5), 6.70 (t, 1H, C6H5), 7.11 (t, 2H, C6H5), 7.26–7.36 (m, 3H,