A green one-pot three-component synthesis of α-aminophosphonates under solvent-free conditions and ultrasonic irradiation using Fe3O4@SiO2-imid-PMAn as magnetic catalyst

Article abstract of DOI:10.1080/10426507.2016.1269232

An efficient and environment friendly process for the synthesis of α-aminophosphonates has been devised. Through a one-pot three-component condensation of various aldehydes, amines, and triethyl phosphite in the presence of Fe₃O₄@SiO₂-imid-PMAn nanoparticles as magnetic catalysts under solvent-free conditions and ultrasonic irradiation, α-aminophosphonates were obtained with excellent yields. The reactions under solvent-free conditions at room temperature are compared with the ultrasonic-assisted reactions. This new procedure has notable advantages such as short reaction time, excellent yields, easy purification, and the absence of any tedious workup or purification. The aforementioned catalyst could be easily recovered by an external magnetic field and can be reused for six consecutive reaction cycles without significant loss of activity. In addition, SEM and DLS of the catalyst after the reaction cycle were investigated.

Full text of DOI:10.1080/10426507.2016.1269232

ACCEPTED MANUSCRIPT
Fe3O4@SiO2-imid-PMAn catalyzed synthesis of α-aminophosphonates.
A green one-pot three-component synthesis of α-aminophosphonates under solvent-free
conditions and ultrasonic irradiation using Fe3O4@SiO2-imid-PMAn as magnetic catalyst
Mohsen Esmaeilpour*,a, Saeed Zahmatkesh*,b, Jaber Javidic, Elahe Rezaeib
aChemistry Department, College of Science, Shiraz University, Shiraz, Iran
bDepartment of Science, Payame Noor University (PNU), 19395-4697, Tehran, Islamic Republic
of Iran
cDepartment of Pharmaceutics, School of Pharmacy, Shahid Beheshti University of Medical
Sciences, Tehran, Iran
*Corresponding author. Tel.: +98 7136137738, fax: +98 7132286008. E-mail address: E-mail
address: m1250m551085@yahoo.com (M. Esmaeilpour), zahmatkesh1355@yahoo.com (S.
Zahmatkesh)
Abstract
An efficient and environment friendly process for the synthesis of α-aminophosphonates has
been devised. Through a one-pot three-component condensation of various aldehydes, amines,
and triethyl phosphite in the presence of Fe3O4@SiO2-imid-PMAn nanoparticles as magnetic
catalysts under solvent-free conditions and ultrasonic irradiation, α-aminophosphonates were
obtained with excellent yields. The reactions under solvent-free conditions at room temperature
are compared with the ultrasonic-assisted reactions. This new procedure has notable advantages
such as short reaction time, excellent yields, easy purification, and absence of any tedious
workup or purification. The aforementioned catalyst could be easily recovered by an external
1
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
magnetic field and can be reused for six consecutive reaction cycles without significant loss of
activity. In addition, SEM and DLS of the catalyst after the reaction cycle were investigated.
GRAPHICAL ABSTRACT
Keywords
α-Aminophosphonates; Multi-component reaction; One-pot synthesis; Solvent-free reaction;
Green synthesis; Ultrasonic irradiation.
2
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
1. Introduction
α-Aminophosphonates are structurally analogous to amino acids. They have been found to
exhibit a pivotal role in synthetic organic chemistry as well as in medicinal chemistry.[1,2] The
medicinal importance and biological effects of α-aminophosphonate derivatives, such as
antithrombotic agent,[3] anticancer agent,[4] antihypertensive agents,[5] anti-inflammatory agent,[6]
catalytic antibodies,[7] potential antioxidants,[1] antibiotic,[4] biotryticides[8] enzyme inhibitors,[9]
carriers of hydrophilic organic molecules across phospholipid membranes,[10] HIV protease,[11]
and peptidases and proteases[12] have stimulated scientific research to develop many synthetic
procedures for them. Also, they can be used as fungicides,[13] herbicides,[14] insecticides,[15] plant
virucides[16] and hypothetical radio protecting agent.[17] These methods include the use of
Brønsted acids such as Amberlite-IR 120,[18] sulfamic acid,[19] hypophosphorus acid,[20]
CF3CO2H,[21] oxalic acid[22] and Lewis acids such as Al(H2PO4)3,[23] Na2CaP2O7,[24] LiClO4,[25]
[33]
SbCl3/Al2O3,[26] InCl3,[27] BiCl3,[28] ZrCl4,[29] FeCl3,[30] SiO2@TaCl5,[31] TiO2,[32] Yb(PFO)3
(bromodimethyl)sulfonium bromide[34] and trimethylanilinium chloride.[35] However, many of
the reported synthetic protocols for the synthesis of α-aminophosphonates suffer from one or
more disadvantages such as using toxic, expensive and moisture sensitive catalysts, long reaction
times, poor yields, harsh reaction conditions, tedious separation procedures and the use of heavy
metal catalysts. Therefore, the development of a new catalytic system to overcome these
shortcomings and fulfill the criteria of an effective, convenient, and green protocol for the
synthesis of α-aminophosphonates is still a challenge.
In recent years, magnetite (Fe3O4) nanoparticles have attracted increasing interest due to the
interesting properties including a low toxicity, superparamagnetism, biocompatibility, large
3
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
surface to volume ratio and wide application range including magnetic resonance imaging,
targeted gene therapy, magnetic data storage, drug delivery systems, biosensors, environmental
remediation, ion exchange separation, magnetic bioseparations, treatment of cancer and
catalysis.[36-40] For many applications, magnetic nanoparticles are suitable because they are
chemically stable and uniform in size. Nevertheless, magnetic nanoparticles easily aggregate
because of anisotropic dipolar attraction and alter their magnetic properties. Therefore, a
protection layer is important to avoid such limitations from occurring.[41] For this purpose, silica
has been widely used because of its stability under different reaction conditions and due to the
fact that it can be easily functionalized for diverse applications.[42] Recently, surface
functionalized magnetic nanoparticles have been developed in a range of organic
transformations, and the studies on immobilization of organo catalysts on core-shell
nanoparticles have been reported.[43-46]
In our previous study,[47] H3PMo12O40 nanoparticles were synthesized and these nano-
heteropolyacids were immobilized onto the imidazole functionalized Fe3O4@SiO2 nanoparticles.
Compared to other substrates (silica, active carbon, nano-titania and acidic ion-exchange resins),
Fe3O4@SiO2-imid nanoparticles have various advantages such as low leaching, high loading
capacity and simple and efficient recovery procedure. Fig. 1 presents the procedure for the
stepwise preparation of Fe3O4@ SiO2-imid-PMAn.
In the present research, we describe an efficient, facile, and convenient procedure for the
synthesis of α-aminophosphonates by condensation of various aldehydes with amines and
triethyl phosphite in the presence of Fe3O4@SiO2-imid-PMAn in a one-pot three-component
synthesis under solvent-free conditions and ultrasonic irradiation at room temperature.
4
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
2. Results and discussions
In our previous work,[47] the Fe3O4, Fe3O4@SiO2 and Fe3O4@SiO2-imid-PMAn nanocatalysts
were characterized by various methods such as transmission electron microscopy (TEM),
scanning electron microscopy (SEM), dynamic light scattering (DLS), Fourier transform infrared
(FT-IR), vibrating sample magnetometer (VSM) etc. The presence of vibration bands at 556,
794, 864, 956,1055,1095, 1454 and 2792-2985 cm1 which is due to the FeO, MoOeMO,
MoOcMO, MoOt, PO, SiOSi, C = N and CH bonds respectively, demonstrates the
existence of Fe3O4@SiO2-imid-PMAn (Fig. 1).[47] Fig. 1 shows the XRD pattern for
Fe3O4@SiO2-imid-PMAn nanoparticles. For Fe3O4@SiO2-imid-PMAn nanoparticles, the
presence of the silica and imid-PMAn layers on the Fe3O4 nanoparticles, leads to an amorphous
structure and the disappearance of peaks corresponding to Fe3O4 and PMAn.[47] The magnetic
properties of nanoparticles were measured by VSM at room temperature. The saturation
magnetization of Fe3O4, Fe3O4@SiO2 and Fe3O4@SiO2-imid-PMAn is 63.4, 39.7, 33.2 emu/g,
respectively.[47] As shown in Fig. 1, Fe3O4@SiO2-imid-PMAn nanoparticles have spherical
shapes with approximately 50 nm diameters. The size distribution of these is centered at a value
of 55 nm.[47]
In continuation of our research work of developing methods in various organic
transformations, herein we describe Fe3O4@SiO2-imid-PMAn as a heterogeneous acid catalyst
for the synthesis of α-aminophosphonates in a one-pot reaction under solvent-free reaction
conditions or ultrasonic irradiation at room temperature (Scheme 1).
Initially, we attempted the one pot coupling of benzaldehyde (1 mmol), aniline (1 mmol), and
triethyl phosphite (1.2 mmol) as the model reaction to optimize the reaction conditions. First, we
5
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
examined the reaction in the presence of varying amounts of the catalyst. The results are
presented in Table 1. The best result was achieved by carrying out the reaction with a (0.015 g:
1 mmol: 1 mmol: 1.2 mmol) ratio of Fe3O4@SiO2-imid-PMAn catalyst, benzaldehyde, aniline
and triethyl phosphite under solvent free conditions at room temperature (Table 1, entry 4). Use
of a higher amount of the catalyst did not improve the yield (Table 1, entry 5) while a decrease of
the amount of catalyst resulted in lower yields under the same conditions (Table 1, entries 2, 3).
The results show clearly that the catalyst is effective for this transformation. In the absence of the
catalyst the reaction did not take place even after longer reaction times (Table 1, entry 1).
Then, we conducted the reactions in CH2Cl2, CHCl3, CH3CN, THF, Et2O, EtOH,
C2H5OH/H2O and H2O as solvents and under solventless conditions (Table 1, entries 4 and 6-
13). The presented data in Table 1 show that the reaction proceeded efficiently under solvent-
free conditions and resulted in high yields of the desired product (Table 1, entry 4).
To investigate the ability of ultrasonic irradiation for the acceleration of the reaction, we
examined the model reaction under ultrasonic irradiation at room temperature and with various
amounts of catalyst. As shown in Table 1, the best results were obtained in the presence of 0.005
g of catalyst (Table 1, entry 15).
However, the synthesis of organic compounds under ultrasound irradiation is been limited by the
need of a specialized apparatus that may not be available in many laboratories. Because of this
limitation, herein we report both ultrasonic irradiation in the presence of 0.005 g of catalyst and
also under solvent-free conditions in the presence of 0.015 g of catalyst at room temperature for
the synthesis of α-aminophosphonates.
6
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Due to the above observations, a range of various aldehydes and amines was investigated
to determine the method’s scope and limitations. The results are summarized in Table 2.
Aromatic aldehydes substituted with either electron-withdrawing or electron-donating groups
underwent the reaction smoothly and gave the products in excellent yields, whereas aliphatic
aldehydes afforded phosphonates in good yields, which is expected that aromatic aldehydes have
higher reactivity than aliphatic aldehydes. In conclusion, aldehydes bearing electron-
withdrawing groups required shorter times and gave higher yields (Table 2). The reactivity of
heterocyclic aldehydes such as furan-2-carbaldehyde and thiophene-2-carbaldehyde with
aromatic amines produced the corresponding products in excellent yields (Table 2, entries 20,
21). Moreover, in all of the above cases, ultrasonic irradiation gave comparable yields of
products but within shorter reaction times, compared to solvent-free conditions at room
temperature.
To demonstrate the value of the present work in comparison with some of the reported catalysts in the
literature, the data on the reaction between benzaldehyde, aniline and triethyl phosphite are summarized in
Table 3. This study showed that Fe3O4@SiO2-imid-PMAn performs its catalytic role in a shorter reaction
time and gives a higher yield of the desired product under solvent-free conditions and ultrasonic irradiation
at room temperature (Table 3, entry 10). Moreover, some of the catalysts listed in Table 3 are not reusable
and thus our reusable catalyst and methodologies represent a better alternative compared to the reported
methods for the production of the corresponding products.
The magnetic separability of the prepared magnetic catalyst was tested in ethyl acetate solution
by placing a magnet beside the glass cylinder. As displayed in Fig. 2a, without an outer magnet,
Fe3O4@SiO2-imid-PMAn prepared could be well dispersed in ethyl acetate solution to form a
7
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
suspension. With the aid of an external magnetic field, the nanoparticles were attracted to the
magnet and separated easily from the solution, which suggest that the catalyst possesses good
separability and magnetism.
The recovery and reusability of the catalyst were examined in the synthesis of α-
aminophosphonates (Fig 2b). After the separation of products, the catalyst was washed with
ethanol, dried and stored for another consecutive reaction run. The activity of the catalyst did not
get much affected in terms of yields after six successive runs for the model reaction. It revealed
that the catalyst displayed very good reusability.
SEM and DLS images of the catalyst after the sixth synthesis cycle of α-aminophosphonate
(1a) under solvent-free conditions at room temperature are shown in Fig. 2c,d. The SEM image
shows that the nanoparticles exhibit approximately spherical shapes. Additionally, the
hydrodynamic diameter of catalyst was investigated by use of the DLS technique. As shown in
Fig. 2d, a narrow size distribution of Fe3O4@SiO2-imid-PMAn NPs was obtained with a mean
diameter of around 65 nm. Generally, the size of catalysts will be increased after each cycle and
leaching of H3PMo12O40 and the increase of the catalyst size leads to decreases in the yield.
2. Experimental
2.1. Materials and physical measurements
All chemicals were purchased from Merck, Fluka or Acros Chemical Companies in high purity
and used without any further purification. The 1H NMR and 13C NMR spectra were recorded on
a Bruker Avance DPX 250 MHz Spectrometer in CDCl3 solvent using TMS as an internal
standard reference. Fourier transform infrared spectroscopy (FT-IR) analysis of the samples was
taken on a Shimadzu FT-IR 8300 spectrophotometer and the sample and KBr were pressed to
8
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
form a tablet. Scanning electron microscopy (SEM) image was obtained on Philips XL-30ESEM.
Dynamic light scatterings (DLS) were recorded on a HORIBALB550. Sonication was performed
using an ultrasound cleaning bath (KQ-250B, China) with a frequency of 30 Hz and voltage of
220 V. Melting points were determined with a Buchi 510 instrument in open capillary tubes and
are uncorrected. Determination of the purity of the substrate and monitoring of the reaction were
accomplished by thin layer chromatography (TLC) on a silica gel polygram SILG/UV 254
plates. All products were identified by comparison of their spectral data and physical properties
with those of the authentic sample and all yields refer to isolated products. The Supplemental
1
13
Materials contains characterization data and sample H and C NMR spectra (Figures S 1 -- S
8).
2.2. General procedure
2.2.1. Preparation of Fe3O4@SiO2-imid-PMAn
Fe3O4@SiO2-imid-PMAn nanoparticles were prepared in our previous work.[59-64]
2.2.2. General procedure for synthesis of α-aminophosphonates
To a mixture of aldehyde (1 mmol), amine (1 mmol) and triethyl phosphite (1.2 mmol) was
added Fe3O4@SiO2-Imid-PMAn (0.015 g or 0.005 g), and the mixture was stirred under solvent-
free conditions or sonicated at room temperature for a particular period of time as given in Table
2. The progress of the reaction was monitored by TLC (eluent: EtOAc/n-hexane, 30:70). After
the reaction was complete, EtOAc (2×5 mL) was added to the reaction mixture and the catalyst
was separated by magnetic field. The filtrate was dried and the organic medium was removed
with a rotary evaporator under reduced pressure. The residue was purified by silica gel column
9
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
chromatography eluting with n-hexane-ethyl acetate (7:3) to afford the corresponding pure α-
aminophosphonate.
4. Conclusion
In conclusion, the present communication reports an efficient green synthesis of α-
aminophosphonates in excellent yield with short reaction times via one-pot three-component
reaction in the presence of Fe3O4@SiO2-imid-PMAn nanoparticles under solvent free or
ultrasound conditions at room temperature. Short reaction time achieved by ultrasonication is an
additional advantage of this reaction. This method provides notable advantages such as easy
preparation, easy separation, thermal stability, and heterogeneous nature of the catalyst, easy
product separation and purification, solvent-free conditions, excellent yields of desired products,
short reaction times, lower loading of catalyst compared with the other methods and hence
environmentally benign methodology that makes this method a useful and attractive process for
the synthesis of these important compounds. In addition, the catalyst was recycled and reused six
times by using an external permanent magnet without considerable loss of catalytic activity.
Selected spectral data
Diethyl (phenyl)(phenylamino)methanephosphonate (1a)
White solid, M.P. = 85-86°C (lit. 86°C);[32,65] 1H NMR (250 MHz, CDCl3) δ: 1.05 (t, 3H, JH,H
=
7.1 Hz, OCH2CH3), 1.28 (t, 3H, JH,H = 7.1 Hz, OCH2CH3), 3.60-3.67 (m, 1H, OCH2CH3), 3.90-
3.92 (m, 1H, OCH2CH3), 4.05-4.14 (m, 2H, OCH2CH3), 4.74 (d, 1H, 2JP,H = 26.4 Hz, CHP), 4.82
(br s, 1H, NH), 6.57-6.69 (m, 3H, ArH), 7.04 (t, 2H, JH,H = 7.2 Hz, ArH), 7.22-7.33 (m, 3H,
ArH), 7.45-7.47 (d, 2H, JH,H = 7.2 Hz, ArH) ppm; 13C NMR (62.9 MHz, CDCl3) δ: 16.1 (d, 3JC,P
= 6.2 Hz, OCH2CH3), 16.3 (d, 3JC,P = 6.2 Hz, OCH2CH3), 54.8 (d, 1JC,P = 150.0 Hz, CP), 63.2 (d,
10
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
2JC,P = 6.5 Hz, OCH2CH3), 63.3 (d, 2JC,P = 6.5 Hz, OCH2CH3), 113.8, 118.3, 127.8, 127.8, 128.5,
128.5, 129.1, 135.9, 146.2, 146.4 (ArH) ppm; 31P NMR (120 MHz, CDCl3): δ = 21.066 ppm; MS
(70 eV), m/e: 319 (M+), 182 [M-P(O)(OEt)2]. Anal. Calcd for C17H22NO3P: C, 63.95; H, 6.89; N,
4.39; Found: C, 63.88; H, 6.99; N, 4.30%.
Diethyl (phenyl)-N-(4-methylphenylamino)methanephosphonate (1b)
White solid; M.p. = 116 C (lit.117-118 C);[33] 1H NMR (250 MHz, CDCl3) δ: 1.15 (t, 3H, JH,H
= 7.0 Hz, OCH2CH3), 1.31 (t, 3H, JH,H = 7.0 Hz, OCH2CH3), 2.21 (s, 3H, CH3), 3.70-3.76 (m,
1H, OCH2CH3), 3.92-4.02 (m, 1H, OCH2CH3), 4.11-4.20 (m, 2H, OCH2CH3), 4.72-4.82 (m, 2H,
CH, NH), 6.55 (d, 2H, JH,H = 8.2 Hz, ArH), 6.94 (d, 2H, JH,H = 8.1 Hz, ArH), 7.29-7.38 (m, 3H,
13
3
ArH), 7.48-7.51 (m, 2H, ArH) ppm; C NMR (62.9 MHz, CDCl3) δ: 16.6 (d, JC,P = 5.8 Hz,
3
1
OCH2CH3), 16.8 (d, JC,P = 5.8 Hz, OCH2CH3), 20.76 (CH3), 56.7 (d, JC,P = 150.4 Hz, CH),
63.6-63.7 (OCH2CH3), 114.4, 128.0-130.1, 136.4, 144.2-144.5 (ArH) ppm; MS (70 eV), m/e:
333 (M+), 196 [M  diethyl(phenyl)-N-(phenyl)aminomethanephosphonate P(O)(OEt)2]; Anal.
Calcd for C18H24NO3P: C, 64.85; H, 7.26; N, 4.20; Found: C, 64.79; H, 7.21; N, 4.13%.
Diethyl (4-hydroxyphenyl)(phenylamino)methanephosphonate (1e)
Viscous colorless oil;[32] 1H NMR (250 MHz, CDCl3) δ: 0.89 (t, 3H, 2JH,H = 7.1 Hz, OCH2CH3),
1.04-1.12 (t, 3H, JH,H = 7.1 Hz, OCH2CH3), 3.48-3.54 (m, 1H, OCH2CH3), 3.70-3.76 (m, 1H,
2
OCH2CH3), 3.84-3.91 (m, 2H, OCH2CH3), 4.55 (d, 1H, JP,H = 23.6 Hz, CHP), 4.96 (s, 1H,
PhOH), 5.45 (br s, 1H, NH), 6.40-6.50 (m, 3H, ArH), 6.64 (d, 2H, JH,H = 6.5 Hz, ArH), 6.86 (d,
31
2H, JH,H = 7.1 Hz, ArH), 7.08 (d, 2H, JH,H = 6.5 Hz, ArH) ppm; P NMR (120 MHz, CDCl3): δ
= 21.29 ppm; Anal. calcd for C17H22NO4P: C, 60.89; H, 6.61; N, 4.18; Found: C, 60.77; H, 6.54;
N, 4.09%.
11
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Diethyl (4-methoxyphenyl)(phenylamino)methanephosphonate (1f)
Viscous colorless oil;[52,65] 1H NMR (250 MHz, CDCl3) δ: 1.10, (t, 3H, JH,H = 7.0 Hz,
OCH2CH3), 1.24, (t, 3H, JH,H = 7.1 Hz, OCH2CH3), 3.75 (s, 3H, OCH3), 3.67-3.71, (m, 1H,
OCH2CH3), 3.89-3.96, (m, 1H, OCH2CH3), 4.06-4.14, (m, 2H, OCH2CH3), 4.67-4.76 (m, 2H,
CHP, NH), 6.57-6.70 (m, 3H, ArH), 6.83 (d, 2H, JH,H = 10.0 Hz, ArH), 7.06 (t, 2H, JH,H = 7.5,
ArH), 7.35-7.40 (m, 2H, ArH) ppm; 13C NMR (62.9 MHz, CDCl3) δ: 16.2 (d, 3JC,P = 5.6 Hz,
OCH2CH3), 16.4 (d, 3JC,P = 5.6 Hz, OCH2CH3), 54.1 (d, 1JC,P = 150.0 Hz, CP), 55.2 (OCH3), 63.2
2
(d, JC,P = 6.5 Hz, OCH2CH3), 113.9, 114.1, 118.3, 127.6, 128.9, 129,0, 129.1, 146.2, 146.5,
31
159.3 (ArH) ppm; IR (KBr, Cm−1): 3292 (NH), 1231 (P = O), 1049 (P-OEt); P NMR (120
MHz, CDCl3): δ = 21.284 ppm; MS (70 eV), m/e: 349 (M+), 212 [M-P(O)(OEt)2]; Anal. Calcd
for C18H24NO4P: C, 61.88; H, 6.92; N, 4.01; Found: C, 61.79; H, 6.98; N, 3.94%.
Diethyl(4-methoxyphenyl)(4-methoxyphenylamino)methanephosphonate (1h)
White solid, M.p. = 120-121°C (lit. 118°C);[32] 1H NMR (250 MHz, CDCl3) δ: 1.09 (t, 3H, JH,H
=
7.0 Hz, OCH2CH3), 1.27 (t, 3H, JH,H = 7.0 Hz, OCH2CH3), 3.40 (s, 6H, OCH3), 3.62-3.70 (m,
1H, OCH2CH3), 3.87-3.92 (m,1H, OCH2CH3), 4.03-4.12 (m, 2H, OCH2CH3), 4.62 (d,1H, 2JP,H
=
24.2 Hz, CHP), 5.45 (br s, 1H, -NH), 6.51 (d, 2H, JH,H = 7.5 Hz, ArH), 6.67 (d, 2H, JH,H = 7.2 Hz,
31
ArH), 6.96 (d, 2H, JH,H = 8.5 Hz, ArH), 7.20 (d, 2H, JH,H = 8.5 Hz, ArH) ppm; P NMR (120
MHz, CDCl3) δ = 22.3 ppm; MS (70 eV), m/e: 379, 253, 241, 226, 171, 184, 128, 92, 77; Anal.
Calcd for C19H26NO5P: C, 60.16; H, 6.86; N, 3.69; Found: C, 60.05; H, 6.76; N, 3.61%.
Diethyl (4-methoxyphenyl) (4-nitrophenyl amino)methanephosphonate (1i)
Yellow solid, M.p. = 114-115°C (lit. 115°C);[66] 1H NMR (250 MHz, CDCl3) δ: 0.89 (t, 3H, JHH
= 7.1 Hz, OCH2CH3), 0.97 (t, 3H, JHH = 7.1 Hz, OCH2CH3), 3.42 (s, 3H, PhOMe), 3.81-3.90 (m,
12
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
2
4H, OCH2CH3), 4.55 (d, 1H, JHP = 23.7 Hz, CHP), 6.38 (d, 2H, JH,H = 9.1 Hz, ArH), 6.55 (d,
2H, JH,H = 8.5 Hz, ArH), 6.65 (br s, 1H, NH), 7.13 (dd, 2H, JH,H = 8.5, 2.1 Hz, ArH), 7.96 (d, 2H,
31
JH,H = 9.1 Hz, ArH); P NMR (120 MHz, CDCl3) δ = 22.2 ppm; Anal. Calcd for C18H23N2O6P:
C, 54.82; H, 5.88; N, 7.10; Found: C, 54.78; H, 5.83; N, 7.06%.
Diethyl (phenylamino)(p-tolyl)methanephosphonate (1l)
White solid, M.p. = 61-62°C (lit. 60°C);[32] 1H NMR (250 MHz, CDCl3) δ: 0.97 (t, 3H, JH,H = 7.0
Hz, OCH2CH3),1.10 (t, 3H, JH,H = 7.0 Hz, OCH2CH3), 2.12 (s, 3H, PhCH3), 3.52-3.55 (m, 1H,
2
OCH2CH3), 3.73-3.80 (m, 1H, OCH2CH3), 3.92-4.00 (m, 2H, OCH2CH3), 4.61 (d, 1H, JP,H
=
24.1 Hz, CHP), 4.97 (br s, 1H, NH), 6.44-6.53 (m, 3H, ArH), 6.79-7.02 (m, 4H, ArH), 7.22 (d,
31
2H, ArH) ppm; P NMR (120 MHz, CDCl3) δ = 19.89 ppm; Anal. Calcd for C18H24NO3P: C,
64.85; H, 7.26; N, 4.20; Found: C, 64.78; H, 7.21; N, 4.16%.
Diethyl (4-chlorophenyl)(phenylamino)methanephosphonate (1m)
White solid, M.p. = 55-57°C (lit. 57°C);[32] 1H NMR (250 MHz, CDCl3) δ: 1.12 (t, 3H, JH,H = 7.1
Hz, OCH2CH3), 1.25 (t, 3H, JH,H = 7.1 Hz, OCH2CH3), 3.69-3.79 (m, 1H, OCH2CH3), 3.96-4.0
(m, 1H, OCH2CH3), 4.09-4.15 (m, 2H, OCH2CH3), 4.60-4.77 (m, 2H, CHP, NH), 6.54 (d, 2H,
JH,H = 7.8 Hz, ArH), 6.57 (t, 1H, JH,H = 7.3 Hz, ArH), 7.03 (t, 2H, JH,H = 7.8 Hz, ArH), 7.28-7.32
(m, 2H, ArH), 7.39-7.43 (m, 2H, ArH) ppm; 13CNMR (62.9 MHz, CDCl3) δ: 16.2 (d, 3JC,P = 5.6
Hz, OCH2CH3), 16.4 (d, 3JC,P = 5.6 Hz, OCH2CH3), 54.3 (d, 1JC,P = 150, CP), 63.3 (d, 2JC,P = 6.5
2
Hz, OCH2CH3), 63.4 (d, JC,P = 6.5 Hz, OCH2CH3), 113.8, 118.6, 128.8, 129.1, 129.2, 129.2,
133,7, 134.6, 145.8, 146.1 (ArH) ppm; 31P NMR (120 MHz, CDCl3) δ = 20.00 ppm; MS (70
eV), m/e: 353 (M+), 355 (M+2), 216 [M-P(O)(OEt)2]; Anal. Calcd for C17H21ClNO3P: C, 57.72;
H, 5.98; N, 3.96; Found: C, 57.64; H, 5.91; N, 3.88%.
13
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Diethyl (2-chlorophenyl)(phenylamino)methanephosphonate (1n)
White solid, M.p. = 89 C (lit. 88-90°C);[66] 1H NMR (250 MHz, CDCl3) δ: 0.95 (t, 3H, JH,H
=
7.0 Hz, OCH2CH3), 1.20 (t, 3H, JH,H = 6.9 Hz, OCH2CH3), 3.53-3.56 (m,1H, OCH2CH3), 3.75-
3.82 (m, 1H, OCH2CH3), 4.09- 4.15 (m, 2H, OCH2CH3), 5.33 (d, 1H, 2JH,P = 24.8 Hz, CHP), 6.4
(br s, 1H, NH), 6.56 (d, 2H, JH,H = 7.8 Hz, ArH), 6.58 (t, 1H, JH,H = 7.2 Hz, ArH), 6.95-7.10 (m,
31
6H, ArH); P (120 MHz, CDCl3): δ = 20.01 ppm; Anal. Calcd for C17H21ClNO3P: C, 57.72; H,
5.98; N, 3.96; Found: C, 57.65; H, 5.91; N, 3.89%.
Diethyl (4-bromophenyl)(phenylamino)methanephosphonate (1o)
White solid; M.p. = 66-67 C (lit. 66-68°C);[59] 1H NMR (250 MHz, CDCl3) δ: 1.17 (t, 3H, JH,H
=
8.75 Hz, OCH2CH3), 1.28 (t, 3H, JH,H = 8.75 Hz, OCH2CH3), 3.69-3.79 (m, 1H, OCH2CH3),
4.09-4.13 (m, 3H, OCH2CH3), 4.66-4.76 (m, 2H, CHP, NH), 6.53-6.57 (m, 3H, ArH), 7.10 (t,
2H, JH,H = 7.5 Hz, ArH), 7.33-7.76 (m, 4H, ArH) ppm; 13CNMR (62.9 MHz, CDCl3) δ: 16.2 (d,
3JC,P = 5.6 Hz, OCH2CH3), 16.4 (d, 3JC,P = 5.6 Hz, OCH2CH3), 54.4 (d, 1JC,P = 150, CP), 63.2 (d,
2JC,P = 6.5 Hz, OCH2CH3), 63.4 (d, 2JC,P = 6.5 Hz, OCH2CH3), 113.8, 118.6, 121.8, 121.9, 129.2,
31
129.4, 129.5, 131,7, 131.8, 135.1, 145.8, 146.1 (ArH) ppm; P NMR (120 MHz, CDCl3): δ =
20.197 ppm; MS (70 eV), m/e: 399, 397 (M+); Anal. Calcd for C17H21BrNO3P: C, 51.27; H,
5.28; N, 3.52; Found: C, 57.18; H, 5.21; N, 3.43%.
Diethyl (4-nitrophenyl)(phenylamino)methanephosphonate (1q)
Bright yellow solid, M.p. = 121-122°C (lit. 120°C);[32] 1H NMR (250 MHz, CDCl3) δ: 1.16 (t,
3H, JH,H = 6.9 Hz, OCH2CH3), 1.26 (t, 3H, JH,H = 6.9 Hz, OCH2CH3), 3.86-4.17 (m, 4H,
2
OCH2CH3), 4.90 (d, 1H, JP,H = 25.2 Hz, CHP), 5.21 (br s, 1H, NH), 6.55 (d, 2H, JH,H = 7.7 Hz,
ArH), 6.67 (t, 1H, JH,H = 7.1 Hz, ArH), 7.06 (t, 2H, JH,H = 7.1 Hz, ArH), 7.66 (dd, 2H, JH,H = 8.5,
14
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
2.2 Hz, ArH), 8.13 (d, 2H, JH,H = 8.5 Hz, ArH) ppm; IR (KBr, cm−1): 3287 (NH), 1232 (P = O),
1054 (P-OEt); 31P (120 MHz, CDCl3): δ = 21.4 ppm; MS (70 eV), m/e: 364.12 (M+), 226; Anal.
Calcd for C17H21N2O5P: C, 56.04; H, 5.81; N, 7.69; Found: C, 55.91; H, 5.73; N, 7.52%.
Diethyl (3-nitrophenyl)(phenylamino)methanephosphonate (1s)
Yellow crystalline solid, M.p. = 97-98°C(lit. 95-97°C);[33] 1H NMR (250 MHz, CDCl3) δ: 1.09
(t, 3H, JH,H = 7.0Hz, OCH2CH3); 1.20 (t, 3H, JH,H = 7.0 Hz, OCH2CH3), 3.73-4.15 (m, 4H,
2
OCH2CH3), 4.82 (d, 1H, JP,H = 24.8 Hz, CHP), 5.46 (br s, 1H, NH), 6.48-6.65 (m, 3H, ArH),
7.01 (t, 2H, JH,H = 7.8 Hz, ArH), 7.40 (t, 1H, JH,H = 7.5 Hz, ArH), 7.76 (d, 1H, JH,H = 7.7 Hz,
ArH), 8.05 (d, 1H, JH,H = 9.5 Hz, ArH), 8.29 (s, 1H, ArH) ppm; 13C NMR (62.9 MHz,CDCl3) δ:
16.2 (d, 3JC,P = 5.6 Hz, OCH2CH3), 16.4 (d, 3JC,P = 5.6 Hz, OCH2CH3), 56.7 (d, 1JC,P = 150.1 Hz,
CP), 63.4 (d, 2JC,P = 6.9 Hz, OCH2CH3), 63.8 (d, 2JC,P = 6.9 Hz, OCH2CH3), 113.7, 118.8, 122.8,
122.9, 129.2, 133.8, 133.9, 138.8, 138.9, 145.6, 145.8, 148.4 (ArH) ppm; Anal. Calcd for
C17H21N2O5P: C, 56.04; H, 5.81; N, 7.69; Found: C, 55.95; H, 5.71; N, 7.55%.
Diethyl (phenylamino)(thiophen-2-yl)methanephosphonate (1u)
White solid, M.p. = 68-69°C (lit. 70°C);[32] 1H NMR (250 MHz, CDCl3) δ: 0.78 (t, 3H, JH,H = 7.1
Hz, OCH2CH3), 1.10 (t, 3H, JH,H = 7.1 Hz, OCH2CH3), 3.82-4.11 (m, 4H, OCH2CH3), 4.5 (1H,
2
NH), 4.97 (d, 1H, JP,H = 23.65 Hz, CHP), 6.68-6.70 (m, 3H, ArH), 6.89-6.91 (m, 1H, ArH),
3
7.04-7.15 (m, 4H, ArH) ppm; 13C NMR (62.9 MHz, CDCl3) δ: 16.3 (d, JC,P = 5.8 Hz,
OCH2CH3), 16.4 (d, 3JC,P = 5.8 Hz, OCH2CH3), 52.1 (d, 1JC,P = 158.2 Hz, CP), 63.4 (d, 2JC,P = 7.0
2
Hz, OCH2CH3), 63.6 (d, JC,P = 7.0 Hz, OCH2CH3), 114.0, 118.9, 124.0, 125.2, 126.1, 127.1,
129.2, 139.9, 146.1 (ArH) ppm; MS (70 eV): m/e = 325 [M+], 188 [M-P(O)(OEt)2]; Anal. Calcd
for C15H20NO3PS: C, 55.37; H, 6.20; N, 4.31; Found: C, 55.30; H, 6.13; N, 4.26%.
15
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Diethyl (n-propyl)-N-(phenyl)aminomethanephosphonate (1w)
Viscous colourless oil;[52] 1H NMR (250 MHz, CDCl3) δ: 0.84 (t, 3H, JH,H = 7.2 Hz, CH3), 1.09-
1.24 (m, 6H, OCH2CH3), 1.50-1.82 (m, 4H, (CH2)2CH3), 3.60-3.65 (m, 2H, NH, CHP), 3.94-4.09
(m, 4H, OCH2CH3), 6.58 (d, 2H, JH,H = 8.2 Hz, ArH), 6.65 (d, 1H, JH,H = 7.4 Hz, ArH), 7.09 (t,
2H, JH,H = 7.6 Hz, ArH) ppm; MS (70 eV), m/e: 285 (M+), 148 [M-P(O)(OEt)2]; Anal. Calcd for
C14H24NO3P: C, 58.93; H, 8.48; N, 4.91; Found: C, 58.85; H, 8.41; N, 4.84%.
Acknowledgements
Authors are grateful to the council of Iran National Science Foundation and University of Shiraz
for their unending effort to provide financial support to undertake this work.
16
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
References
[1] Kleszczynska, H.; Sarapuk, J. Cell. Biol. Mol. Lett. 2001, 6, 83-91.
[2] Allen, M. C.; Fuhrer, W.; Tuck, B.; Wade, R.; Wood, J. M. J. Med. Chem. 1989, 32, 1652-
1661.
[3] Atherton, F. R.; Hassall, C. H.; Lambert, R. W. J. Med. Chem. 1986, 29, 29-40.
[4] Atherton, F. R.; Hassall, C. H.; Lambert, R. W. J. Med. Chem. 1987, 30, 1603-1609.
[5] Rozenfeld, R.; Iturrioz, X.; Okada, M.; Maigret, B.; Llorens-Cortes, C. Biochemistry 2003,
42, 14785-14793.
[6] Dillard, R. D.; Pavey, D. E.; Benslay, D. N. J. Med. Chem. 1973, 16, 251-253.
[7] Hirschmann, R.; Smith, A. B.; Taylor, C. M.; Benkovic, P. A.; Taylor, S. D.; Yager, K. M.;
Sprengler, P. A.; Venkovic, S. J. Science 1994, 265, 234-237.
[8] Maier, L. Phosphorus Sulfur Silicon Relat Elem. 1990, 53, 43-55.
[9] Lombaert, S. D.; Blanchard, L.; Tan, J.; Sakane, Y.; Berry, C.; Ghai, R. D. Bioorg. Med.
Chem. Lett. 1995, 5, 145-150.
[10] Danila, C. D.; Wang, X.; Hubble, H.; Antipin, I. S.; Pinkhassik, E. Bioorg. Med. Chem. Lett.
2008, 18, 2320-2323.
[11] Peyman, A.; Stahl, W.; Wagner, K.; Ruppert, D.; Budt, K. H. Bioorg. Med. Chem. Lett.
1994, 4, 2601-2604.
[12] Miller, D. J.; Hammond, S. M.; Anderluzzi, D.; Bugg, T. D. H. J. Chem. Soc. Perkin. Trans.
1998, 1, 131-142.
[13] Maier, L.; Spoerri, H. Phosphorus Sulfur Silicon Relat Elem. 1991, 61, 69-75.
17
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
[14] Kleszczynska, H.; Bonarska, D.; Bielecki, K.; Sarapuk, J. Cell. Mol. Biol. Lett. 2002, 7,
929-935.
[15] Emsley, J.; Hall, D. The Chemistry of Phosphorus, Harper & Row, London, 1976.
[16] Song, B. A.; Wu, Y. L.; Yang, S.; Hu, D. Y.; He, X. Q.; Jin, L. H. Molecules 2003, 8, 186-
192.
[17] Sal'keeva, L. K.; Nurmaganbetova, M. T.; Kurmanaliev, O. S.; Gazizov, T. K. Russ. J. Org.
Chem. 2002, 38, 723-725.
[18] Bhattacharya, A. K.; Rana, K. C. Tetrahedron Lett. 2008, 49, 2598-2601.
[19] Mitragotri, S. D.; Pore, D. M.; Desai, U. V.; Wadgaonkar, P. P. Catal. Commun. 2008, 9,
1822-1826.
[20] Kaboudin, B.; Jafari, E. J. Iran. Chem. Soc. 2008, 5, S97-S102.
[21] Akiyama, T.; Sanada, M.; Fuchibe, K. Synlett 2003, 1463-1464.
[22] Vahdat, S. M.; Baharfar, R.; Tajbakhsh, M.; Heydari, A.; Baghbanian, S. M.; Haksar, S.
Tetrahedron Lett. 2008, 49, 6501-6504.
[23] Maghsoodlou, M. T.; Habibi-Khorassani, S. M.; Heydari, R.; Hazeri, N.; Sajadikhah, S. S.;
Rostamizadeh, M. Chin. J. Chem. 2010, 28, 285-288.
[24] Elmakssoudi, A.; Zahouily, M.; Mezdar, A.; Rayadh, A.; Sebti, S. Comt. Rend. Chimie.
2005, 8, 1954-1959.
[25] Azizi, N.; Rajabi, F.; Saidi, M. R. Tetrahedron Lett. 2004, 45, 9233-9236.
[26] Kumar, A. S.; Taneja, S. C.; Hundal, M. S.; Kapoor, K. K. Tetrahedron Lett. 2008, 49,
2208-2212.
[27] Ranu, B. C.; Hajra, A.; Jana, U. Org. Lett. 1999, 1, 1141-1143.
18
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
[28] Zhan, Z. P.; Li, J. P. Synth. Commun. 2005, 35, 2501-2508.
[29] Manjula, A.; Rao, B. V.; Neelakantan, P. Synth. Commun. 2003, 33, 2963-2969.
[30] Rezaei, Z.; Firouzabadi, H.; Iranpoor, N.; Ghaderi, A.; Jafari, M. R.; Jafari, A. A.; Zare, H.
R. Eur. J. Med. Chem. 2009, 44, 4266-4275.
[31] Chandrasekhar, S.; Prakash, S. J.; Jagadeshwar, V.; Narsihmulu, C. Tetrahedron Lett. 2001,
42, 5561-5563.
[32] Hosseini-Sarvari, M. Tetrahedron 2008, 64, 5459-5466.
[33] Tang, J.; Wang, L.; Wang, W.; Zhang, L.; Wu, S.; Mao, D. J. Fluor. Chem. 2011, 132, 102-
106.
[34] Kudrimoti, S.; Bommena, R. V. Tetrahedron Lett. 2005, 46, 1209-1210.
[35] Heydari, A.; Arefi, A. Catal. Commun. 2007, 8, 1023-1026.
[36] Bruce, I. J.; Sen, T. Langmuir 2005, 21, 7029-7035.
[37] Esmaeilpour, M.; Javidi, J.; Nowroozi Dodeji, F.; Hassannezhad, H. J. Iran. Chem. Soc.
2014, 11, 1703-1715.
[38] Alexiou, C.; Jurgons, R.; Schmid, R.; Hilpert, A.; Bergemann, C.; Parak, F.; Iro, H. J.
Magn. Magn. Mater. 2005, 293, 389-393.
[39] Wong, E. W.; Bronikowski, M. J.; Hoenk, M. E.; Kowalczyk, R. S.; Hunt, B. D. Chem.
Mater. 2005, 17, 237-241.
[40] Esmaeilpour, M.; Javidi, J.; Mokhtari Abarghoui, M.; Nowroozi Dodeji, F. J. Iran. Chem.
Soc. 2014, 11, 499-510.
[41] Lei, Z.; Li, Y.; Wei, X. J. Solid. State .Chem. 2008, 181, 480-486.
19
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
[42] Esmaeilpour, M.; Javidi, J.; Dehghani, F.; Nowroozi Dodeji, F. New. J. Chem. 2014, 38,
5453-5461.
[43] Dalaigh, C. O.; Corr, S. A.; Gunko, Y.; Connon, S. J. Angew. Chem. Int. Ed. 2007, 46,
4329-4332.
[44] Schatz, A.; Hager, M.; Reiser, O. Adv. Funct. Mater. 2009, 19, 2109-2115.
[45] Javidi, J.; Esmaeilpour, M.; Nowroozi Dodeji, F. RSC Adv. 2015, 5, 308-315.
[46] Polshettiwar, V.; Luque, R.; Fihri, A.; Zhu, H.; Bouhrara, M.; Basset, J. M. Chem. Rev.
2011, 111, 3036-3075.
[47] Esmaeilpour, M.; Javidi, J.; Zandi, M. Mater. Res. Bull. 2014, 55, 78-87.
[48] Pourjavadi, A.; Hosseini, S. H.; Hosseini, S. T.; Aghayeemeibody, S. A. Catal. Commun.
2012, 28, 86-89.
[49] Kumar, K. S.; Krishna, B. S.; Reddy, C. B.; Reddy, M. V. N.; Reddy, C. S. Arab. J. Chem.
2012, in press, corrected proof available online, 3rd. October 2012.
[50] Bhattacharya, A. K.; Raut, D. S.; Rana, K. C.; Polanki, I. K.; Khan, M. S.; Iram, S. Eur. J.
Med. Chem. 2013, 66, 146-152.
[51] Zhang, Y.; Zhu, C. Catal. Commun. 2012, 28, 134-137.
[52] Sobhani, S.; Safaei, E.; Asadi, M.; Jalili, F. J. Organomet. Chem. 2008, 693, 3313-3317.
[53] Hou, J. T.; Gao, J. W.; Zhang, Z. H. Appl. Organomet. Chem. 2011, 25, 47-53.
[54] Hajinasiri, R.; Hossaini, Z.; Rostami-Charati, F. Heteroat. Chem. 2011, 22, 625-629.
[55] Jafari, A. A.; Nazarpour, M.; Abdollahi-Alibeik, M. Heteroat. Chem. 2010, 21, 397-403.
[56] Subba Reddy, B. V.; Siva Krishna, A.; Ganesh, A. V.; Narayana Kumar, G. G. K. S.
Tetrahedron Lett. 2011, 52, 1359-1362.
20
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
[57] Niralwad, K. S.; Shingate, B. B.; Shingare, M. S. Ultrason. Sonochem. 2010, 17, 760-763.
[58] Agawane, S. M.; Nagarkar, J. M. Tetrahedron. Lett. 2011, 52, 3499-3504.
[59] Javidi, J.; Esmaeilpour, M. Mater. Res. Bull. 2016, 73, 409-422.
[60] Esmaeilpour, M.; Javidi, J. J. Chin. Chem. Soc. 2015, 62, 614-626.
[61] Esmaeilpour, M.; Javidi, J. J. Chin. Chem. Soc. 2015, 62, 328-334.
[62] Javidi, J.; Esmaeilpour, M.; Rajabnia Khansari, M. RSC Adv. 2015, 5, 73268-73278.
[63] Esmaeilpour, M.; Javidi, J.; Dehghani, F.; Nowroozi Dodeji, F. RSC Adv. 2015, 5, 26625-
26633.
[64] Esmaeilpour, M.; Javidi, J.; Zandi, M. New. J. Chem. 2015, 39, 3388-3398.
[65] Disale, S. T.; Kale, S. R.; Kahandal, S. S.; Srinivasan, T. G.; Jayaram, R. V. Tetrahedron
Lett. 2012, 53, 2277-2279.
[66] Xia, M.; Lu, Y. D. Ultrason. Sonochem. 2007, 14, 235-240.
21
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Table 1. Optimization of the amount of catalyst and solvent in a one-pot synthesis of the model
reaction.a
Catalyst amount
(g)
Time
(min)
120
30
Yield
(%)b
-
Entry
Solvent
Conditions
1
-
Solvent-Free P(OEt)3
Solvent-Free P(OEt)3
Solvent-Free P(OEt)3
Solvent-Free P(OEt)3
Solvent-Free P(OEt)3
2
0.005
0.01
77
92
96
93
86
81
78
73
67
78
66
64
82
3
30
4
0.015
0.02
20
5
20
6
0.015
0.015
0.015
0.015
0.015
0.015
0.015
0.015
0.015
CH2Cl2
CHCl3
CH3CN
THF
P(OEt)3
P(OEt)3
P(OEt)3
P(OEt)3
P(OEt)3
P(OEt)3
20
7
30
8
60
9
60
10
11
12
13
14
Et2O
60
C2H5OH
60
C2H5OH/H2O P(OEt)3
H2O P(OEt)3
80
80
Solvent-Free HP(O)(OEt)2
70
Sonication (30
Solvent-Free
15
0.005
4
98
kHz)/P(OEt)3
Sonication (30
Solvent-Free
16
0.01
4
96
kHz)/P(OEt)3
aReaction condition: benzaldehyde (1 mmol), aniline (1 mmol) and triethyl phosphate (1.2
mmol).
bIsolated yield.
22
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Table 2. One-pot synthesis of α-aminophosphonate catalyzed by Fe3O4@SiO2-imid-PMAn.a
Entry R1
R2
Product
Solvent free/rt Ultrasonic/Solvent free/rt Ref.
Time Yield
(min) (%)b
Time
Yield (%)b
(min)
2
1
C6H5
C6H5
20
20
30
20
30
40
40
20
60
20
30
30
15
30
20
15
15
30
20
40
45
45
96
93
90
92
91
94
92
95
92
93
91
89
95
92
95
95
96
88
94
86
91
76
98
96
93
95
92
94
95
97
94
92
95
92
97
91
95
97
95
91
96
91
93
85
[32]
[33]
[48]
[49]
[32]
[32]
[50]
[32]
[49]
[50]
[51]
[32]
[32]
[32]
[51]
[51]
[32]
[48]
[48]
[48]
[32]
[52]
1a
1b
1c
1d
1e
1f
2
C6H5
p-MeC6H4
p-NO2C6H4
C6H5CH2
C6H5
3
3
C6H5
8
4
C6H5
5
5
p-HOC6H4
4
6
p-MeOC6H4 C6H5
o-MeC6H4 C6H5
5
7
7
1g
1h
1i
8
p-MeOC6H4 p-MeOC6H4
p-MeOC6H4 p-NO2C6H4
3
9
9
10
11
12
13
14
15
16
17
18
19
20
21
22
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-ClC6H4
o-ClC6H4
p-BrC6H4
p-BrC6H4
p-NO2C6H4
p-NO2C6H4
n-Butyl
p-MeC6H4
C6H5
3
1j
5
1k
1l
6
C6H5
2
1m
1n
1o
1p
1q
1r
1s
C6H5
4
C6H5
7
p-MeC6H4
C6H5
4
2
p-NO2C6H4
6
m-NO2C6H4 C6H5
Furfuryl C6H5
2-Thiophene C6H5
n-Propyl p-MeOC6H4
2
8
1t
8
1u
1w
12
23
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
aReaction condition: aldehyde (1 mmol), amine (1 mmol), triethyl phosphite (1.2 mmol), Fe3O4@SiO2-
imid-PMAn (0.015 g), solvent free, room temperature or ultrasonic irradiation (30 kHz), Fe3O4@SiO2-imid-
PMAn (0.005 g).
bIsolated yield.
24
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Table 3. Comparison of the catalytic activity of Fe3O4@SiO2-imid-PMAn with the reported catalysts in the
preparation of diethyl (phenyl)(phenylamino)methanephosphonate (1a).
Entry Catalyst
Condition
Time
(min)
30
Yield
(%)a
95
Ref.
1
2
3
4
5
6
7
NbCl5
TiO2
Solvent-free/50°C
Solvent-free/50°C
[53]
[32]
[54]
[48]
[55]
[56]
[52]
3.5h
60
98
Choline chloride·2ZnCl2 Solvent-free/r.t
96
MNP@DSO3H
CeCl3.7H2O
Nano-Fe3O4
[Cu(3,4-
Solvent-free/rt
Solvent-free/rt
Solvent-free/50°C
H2O, 80oC
25min
5h
91
95
48
94
30
96
tmtppa)](MeSO4)4
Solvent-free/rt
Ultrasonic/Solvent-
free/rt
60
15
75
94
Sodium 1-
8
9
[57]
[58]
hexanesulfonate
CeO2
Ultrasonic/Solvent-
free/rt
5
99
Solvent free/r.t
Ultrasonic/Solvent-
free/rt
20
2
96
98
This
10
Fe3O4@SiO2-imid-PMAn
work
aIsolated yield
25
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Fig 1. Process for the preparation and immobilization of H3PMo12O40 nanoparticles (PMAn) on
imidazole functionalized Fe3O4@SiO2 nanoparticles.
26
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Fig 2. (a) Recyclability of Fe3O4@SiO2-Imid-PMAn in the synthesis of 1a; (b) Photographs of
the separation and re-dispersion processes of Fe3O4@SiO2-Imid-PMAn without external
magnetic field and with external magnetic field; (c) and (d) SEM and DLS images of
Fe3O4@SiO2-imid-PMAn nanoparticles after six reaction cycles.
27
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Scheme 1. Fe3O4@SiO2-imid-PMAn catalyzed synthesis of α-aminophosphonates.
28
ACCEPTED MANUSCRIPT