An Eco-friendly Three Component Manifold for the Synthesis of α-Aminophosphonates under Catalyst and Solvent-free Conditions, X-ray Characterization and Their Evaluation as Anticancer Agents

Article abstract of DOI:10.1002/jccs.201500250

A series of α-aminophosphonates were synthesized through one-pot condensation of aryl aldehydes, aryl amines and diethyl phosphite in the absence of any catalyst and organic solvents. All the synthesized α-aminophosphonates were characterized by spectral

Full text of DOI:10.1002/jccs.201500250

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Article
An Eco-friendly Three Component Manifold for the Synthesis of a-Aminophosphonates
under Catalyst and Solvent-free Conditions, X-ray Characterization and Their
Evaluation as Anticancer Agents
Mahdi Mirzaei,a Hossein Eshghi,a* Mohammad Rahimizadeh,a Mehdi Bakavoli,a Maryam M. Matin,b
Minoo Hosseinymehr,b Hadi Amiri Rudbaric and Giuseppe Brunod
aDepartment of Chemistry, Faculty of Sciences, Ferdowsi University of Mashhad, 91775-1436 Mashhad, Iran
bDepartment of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran
cFaculty of Chemistry, University of Isfahan, 81746-73441 Isfahan, Iran
dUniversità degli Studi di Messina, dip. Scienze Chimiche. Viale Ferdinando S. d’Alcontres, 98166 Messina
(Received: Jun. 28, 2015; Accepted: Oct. 8, 2015; Published Online: Nov. 6, 2015; DOI: 10.1002/jccs.201500250)
A series of a-aminophosphonates were synthesized through one-pot condensation of aryl aldehydes, aryl
amines and diethyl phosphite in the absence of any catalyst and organic solvents. All the synthesized
a-aminophosphonates were characterized by spectral and elemental analysis and in the case of compound
4j by X-ray crystallography. Some of these new a-aminophosphonate derivatives were found to have
cytotoxic activity on the cancer cell line DU145 in vitro by the MTT method.
Keywords: Anticancer activity; Catalyst free; Solvent free; a-Aminophosphonates; X-ray analysis.
INTRODUCTION
a-aminophosphonates which are structural analogs
CeCl3.7H2O,31 FeCl3,1 TiO2,32 NaHSO4-SiO2,33 Nano
Fe3O4,34 g-Fe2O3@SiO2-PA,35 DHAA-Fe3O4,36 IRMOF-3
nano,37 Fe/SWCNTs,38 ZrOCl2.8H2O,39 TiCl4,40 VCl3,41
and ethyl ammonium nitrate.42 However, most of these
methods have drawbacks, have drawbacks, because they
use toxic and/or expensive catalysts and polluting organic
solvents, have unsatisfactory yields or involve difficult
preparations, prolonged reaction times and harsh reaction
conditions, therefore researchers have been developed var-
ious eco-friendly method for their synthesis.43-49
of a-amino acid esters are of interest as potential anticancer
drugs,1,2 enzymes inhibitors,3,4 haptens of catalytic anti-
bodies,5-7 pharmacologic agents,6,7 antifungal activity,8 in-
secticides,9 plant growth regulators,10 and anti-HIV agents.11
Several multi-step synthetic approaches for the synthesis
of a-aminophosphonates have been reported in the litera-
ture including alkylation of nucleophilic Schiff bases,
Hofmann rearrangement of substituted phosphonoacetic
esters and conversion of 1-hydroxyphosphonates to the
corresponding a-aminophosphonates.12
As part of our continuous efforts to develop a green,
ecofriendly, general and cost effective protocol for synthe-
sis a-aminophosphonates, we have been reported an effi-
cient and eco-friendly green one-pot multi-component pro-
tocol for the synthesis of a-aminophosphonate derivatives
in excellent yields via a one-pot three component conden-
sation of various aldehydes, amines and diethyl phosphite
under catalyst and solvent-free conditions. The cytotoxic
activity of the newly synthesized a-aminophosphonates
(4a–p) on the cancer cell line DU145 was also studied us-
ing the MTT method and as the result compounds 4b & 4d
proved to be potential cancer cytotoxic agents.
An alternative synthesis of a-aminophosphonates in-
volves nucleophilic addition of phosphite to imine.13-19
However, since many imines are hygroscopic and are not
sufficiently stable for isolation, this method has certain
limitations. The most simple and straightforward synthetic
method for the synthesis of a-aminophosphonates is the
Kabachnik–Fields reaction which involves a one-pot
three-component coupling of an aldehyde, amine and
phosphite ester. In this regard, numerous protocols for the
synthesis of these compounds have been developed using
various Lewis and Brønsted acid catalysts such as sulfonic
catalyst,20 molecular iodine,21 Xanthan Sulfuric Acid,22
DTP/SiO2,23 succinic acid,24 Phenylphosphonic acid,25
SnCl2,26 SiO2-AlCl3,27 InCl3,28 Mg(ClO4)2,29 M(OTf)3,30
RESULTS AND DISCUSSION
We previously reported a catalyst-free method for the
three-component Mannich reaction.48 Now we have ex-
* Corresponding author. Tel: +98-511-879-5457; Email: heshghi@um.ac.ir
Supporting information for this article is available on the www under http://dx.doi.org/10.1002/jccs.201500250
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panded our interest in multi-component reactions through
synthesis of a-aminophosphonates under catalyst and sol-
vent-free conditions (Scheme 1). In order to optimize the
reaction condition, a model reaction was chosen between
4-chloroaniline, 4-diethylaminobenzaldehyde and diethyl
phosphite in the absence of any catalyst at room tempera-
ture. We used freshly distilled materials in these reactions
to minimize the chances of any impurity catalysis. 4-
diethylaminobenzaldehyde was washed carefully with so-
dium bicarbonate solution to remove any acidic impurity.
The reaction produced the desired product after 5 h. Next,
the temperature was optimized in order to minimize the re-
action time. At 50-60 °C the highest yield of the a-
aminophosphonate was obtained.
Based on these observations, we decide to synthesis
novel a-aminophosphonate derivatives in solvent-free and
catalyst-free condition, and to study their biological pro-
perties, so we used p-dimethylaminobenzaldehyde and
p-diethylaminobenzaldehyde to compare biological pro-
perties. It was considered worthwhile to study the gener-
ality of this method by employing several other carbonyl
compounds and amines. The reactions of 4-diethylamino-
benzaldehyde and diethyl phosphite with different amines
under catalyst-free and solvent-free conditions were inves-
tigated. The results of this study are shown in (Table 1, en-
try 1-8). The treatment of 4-(dimethylamino)benzaldehyde
with several substituted aromatic amines under catalyst and
solvent-free conditions was also studied (Table 1, entry
9-16). It is clear that there is no significant electronic effect
on the progress of three-component couplings using differ-
ent substituted aromatic amines. p-methoxyaniline as a re-
active amine (Table 1, entry 8, 16) and p-nitroaniline as a
deactivated substrate (Table 1, entry 7, 15) were equally ef-
ficient substrates.
Catalyst-free and solvent-free coupling of
benzaldehydes and anilines with diethyl
phosphite for synthesis a-aminophospho-
natea
Scheme 1
In order to comprehensively understand the complete
structural features of compounds 4a-4p, the X-ray struc-
ture of the diethyl (((4-bromophenyl) amino) (4-(dimethyl-
amino) phenyl) methyl) phosphonate 4j as an example was
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Synthesis of Novel a-Aminophosphonates
J. Chin. Chem. Soc. 2015, 62, 1087-1096
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Eshghi et al.
obtained (Figure 1). The crystal structure of 4j is triclinic
system with the space group P-1. As seen from (Figure 1),
the P atom has tetrahedral geometry involving two O-ethyl
groups, one Ca atom, and a double bond with O atom. Lo-
cation of the N-H group is in the opposite direction to the
C-H. The C-P and P=O bond lengths are almost compara-
ble with similar structures.50 There is an intermolecular hy-
drogen bond which is N(1)–H(1)L O(1) (symmetry code,
-x + 1, -y, -z + 1), with N(1)–H(1) = 0.83 Å, H(1)L O(1) =
2.23, N(1)L O(1) = 3.038 Å, and N(1)–H(1)L O(1) = 167°.
(Figure 2).
on application to CCDC, 12 Union Road, Cambridge CB2
1EZ, UK, www.ccdc.cam.ac.uk/data-request/cif.
On the basis of kinetic studies, there are two plausible
mechanisms depending on the nature of the reactants
(Scheme 2).49-51 According to one of the suggested mecha-
nisms, at the first stage H-bond is formed between the P=O
function of the phosphite and the NH unit of the electron
with-drawing aniline to follow the imine formation, then
diethylphosphite added to the C=N bond of imine A, to
give a-aminophosphonate 4, the other stage diethylphos-
phite was activated by forming a weak H-bond between the
N atom of electron-donating aniline and P–H function
which leads to the formation of a-hydroxyphosphite B, Fi-
nally, the reaction of a-hydroxyphosphite moiety B be-
tween aniline resulted in dehydration to form the target
compound 4.
Crystallographic data
CCDC 1001926 contains the supplementary crystal-
lographic data for this paper. These data can be obtained
free of charge from the Cambridge Crystallographic Data
Center. Copies of the data can be obtained, free of charge,
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Synthesis of Novel a-Aminophosphonates
Plausible mechanism for the synthesis of
Scheme 2
a-aminophosphonates 4a–p.
compound. The MTT studies showed that the most cyto-
toxic compounds were 4b which has 4-Br, and 4-diethyl-
amino moieties in its structure, with IC50 = 44 mM and 4d
which has 4-Me, and 4-diethyl amino moieties in its struc-
ture, with IC50 = 42 (mM) on DU145 (Table 2). However,
the replacement of the 4-diethylamino group in the ben-
zaldehyde derived moiety of compounds 4b and 4d with a
4-dimethylamino group, resulted in the compounds 4j and
4l with complete loss of activity, and the other compounds
didn’t show significant inhibitory activity. Currently do-
Fig. 1. ORTEP view of the molecular geometry of
compound 4j Ellipsoids have been drawn at the
30% probability level.
Table 2. Comparative cytotoxic effects of compounds 4a-4p on
DU145 prostate Cancer cells after 24, 48, 72 as assessed
by MTT method
IC50 (mg)a
Compound
24h
48h
72h
4a
4b
4c
4d
4e
4f
4g
4h
230 ± 2.4
50 ± 4.4
200 ± 2.3
49 ± 4.4
140 ± 0.75
NAb
235 ± 2.3
46.5 ± 4.3
201 ± 4.5
45 ± 4.2
145 ± 4.2
NAb
232 ± 4.8
48 ± 4.6
204 ± 4.8
42 ± 4.4
142 ± 4.3
NAb
Fig. 2. A pair of hydrogen bonds in a Centro symmet-
ric dimer of 4j.
200 ± 4.3
NAb
NAb
NAb
NAb
NAb
4i
4j
4k
4l
4m
4n
4o
4p
docetaxel
210 ± 2.5
180 ± 2.3
246 ± 4.5
NAb
212 ± 4.4
182 ± 2.7
240 ± 2.4
NAb
246 ± 2.4
NAb
245 ± 1.2
NAb
40 ± 4.4
215 ± 4.2
191 ± 4.9
239 ± 4.7
NAb
Biological activity
The in vitro cytotoxicity of these compounds was
evaluated against DU145 prostate cancer cells by the MTT
method52 The percentage of cell viability was plotted ver-
sus the log of the concentrations, and nonlinear regression
with a variable slope sigmoidal dose-response curve was
generated along with IC50 using Graph Pad Prism V.3
software.
³ 250
³ 250
NAb
NAb
³ 250
NAb
NAb
NAb
44 ± 4.5
30 ± 4.3
a Arithmetic mean ± standard deviation of at least 3 independent
experiments.
The results summarized in Table 2 indicate that
changes of substituents could affect the cytotoxicity of the
b NA: Not active up to significant concentration.
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cetaxel (taxotere), a member of taxane family, is widely
used in chemotherapy to treat advanced stages of prostate
cancer.53 In this study, the cytotoxic effects of docetaxel
were evaluated on DU145 cells and the data are shown in
(Table 2). Its IC50 values were 44, 40 and 30 mM after 24,
48 and 72 h, respectively (Figure 3). According to these
data, compound 4d has the most cytotoxic effects, similar
to docetaxel.
were incubated for 4 h at 37 °C. After this period, the pur-
ple insoluble formazan, produced from yellow MTT by liv-
ing cells, was dissolved in DMSO (150 ml/well) during 2–3
min. The optical density18 of each well was then measured
spectrophotometrically at 540 nm using an ELISA plate
reader (Awareness, USA). All tests were performed in trip-
licates. Since the formation of formazan is correlated with
Biological assays
Materials
DU145 cells were obtained from the Pasteur Institute
(Tehran, Iran) and were grown in RPMI 1640 medium, sup-
plemented with 10% fetal bovine serum (FBS, Gibco, Scot-
land). Cells were incubated at 37 °C in a humidified atmo-
sphere of 10% CO2 in air for 2–3 days before experimental
use. In order to subculture DU145 cells, they were washed
with phosphate buffered saline (PBS) and incubated with
0.25% trypsin/1 mM EDTA for 3–5 min. Then detached
cells were resuspended in fresh serum-containing medium
to inactivate the trypsin, and transferred to new labeled
flasks as required.
Preparation of various concentrations of the selected
product
To prepare different concentrations of 4a-4p (6.25,
12.5, 25, 50, 100, 250 mM), 2 mmol of each powder was
dissolved in 100 ml dimethylsulfoxide (DMSO, Merck,
Germany) and diluted with complete culture medium be-
fore experiments.
In order to exclude the background cytotoxic effects
of the solvent, control treatments were also run with
DMSO only. These controls included 0.25%, DMSO,
equivalent to the DMSO content of their 4a-4p solutions.
In vitro cytotoxicity assay
The reduction of tetrazolium dye, 3-(4,5-dimethyl-
thiazol-2-yl)-2,5-diphenyltetrazolium bromide, by living
cells is used in a rapid drug-screening assay. Briefly, cells
were seeded at a density of 8 ´ 103 cells/well in 96-well tis-
sue culture plates (organic scientific, France, USA). To
identify the half maximal inhibitory concentration (IC50)
values of 4a-4p, DU145 cells were then incubated with in-
creasing concentrations of 4a-4p (6.25, 12.5, 25, 50, 100,
250 mM) for 24, 48 and 72 h, respectively. Docetaxel
(Darou Pakhsh Holding, Iran) was used at the, 6.25, 12.5,
25, 50, 100 and 250 mM concentrations as a positive con-
trol. 5 mg MTT dye (Sigma, Germany) was dissolved in 1
ml (PBS), filtered and used freshly before each experiment.
20 ml MTT solution was then added to each well and plates
Fig. 3. Time-based dose response curves of DU445
prostate cancer cells to (4b), (4d) and docetaxel
(Doc) during 24, 48 and 72 h.
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Synthesis of Novel a-Aminophosphonates
the number of living cells, the OD read-outs from the
treated wells were converted to the percentage of living
cells against controls. This was calculated by dividing the
absorbance of treated cells in each well to the mean ab-
sorbance of controls multiply by 100. The average back-
ground absorbance from control wells (DMSO without
added MTT) was subtracted from MTT-treated samples
and data were plotted as a percentage using Prism v.3 soft-
ware.
Hz, 4H, NCH2CH3), 3.66-4.73 (m, 1H, OCH2CH3), 3.91-3.98 (m,
1
1H, OCH2CH3), 4.07-4.17 (m, 2H, OCH2CH3), 4.60 (dd, JPH
=
23.0 Hz, 2JPH = 7.2 Hz, 1H, CHP), 4.78 (br, 1H, NH), 6.52 (d, J =
8.8 Hz, 2H, Ar-H), 6.63 (d, J = 7.2 Hz, 2H, Ar-H), 7.20 (d, J = 8.8
Hz, 2H, Ar-H), 7.27 (d, J = 7.2 Hz, 2H, Ar-H), 13CNMR (100.64
MHz, CDCl3): d 12.5, 16.2 (d, 3JPC = 5.6 Hz), 16.4 (d, 3JPC = 5.6
Hz), 44.2, 55.3 (d, 1JPC = 152.9 Hz), 63.0 (d, 2JPC = 7.0 Hz), 63.3
2
(d, JPC = 6.9 Hz), 109.8, 111.8, 115.5, 120.9, 128.7, 131.8, (d,
2JPC = 5.0 Hz), 145.6 (d, 3JPC = 14.0 Hz),147.6. 31P (162.03 MHz,
CDCl3): d 23.11. m/z (ESI) 470 (68 %, [M+]. 472 [68%, M++2].
Anal. Calc. for C21H30BrN2O3P: C, 53.74; H, 6.44; N, 5.97.
Found: C, 53.50; H, 6.28; N, 5.74.
EXPERIMENTAL
All solvents and reagents were purchased from Fluka or
Merck Chemical Companies. FT-IR spectra were recorded using
KBr disks on an Avatar 370 FT-IR Thermo-Nicolet spectrometer.
NMR spectra were recorded on a Bruker Avance DPX 400 and
Diethyl (((3-bromophenyl)amino) (4-(diethylamino)
phenyl) methyl) phosphonate (4c): Yield 90%; m.p = 130-131
°C; IR (KBr, cm-1) u: 3294 (NH), 3018, 2974, 1612, 1594, 1523,
1479, 1235 (P=O), 1057 (P-OEt); 1H NMR (400 MHz, CDCl3): d
1.13-1.16 (m, 3H, OCH2CH3, 6H, NCH2CH3), 1.30 (t, J = 7.0 Hz,
3H, OCH2CH3), 3.34 (q, J = 7.0 Hz, 4H, NCH2CH3), 3.63-3.72
(m, 1H, OCH2CH3), 3.90-3.99 (m, 1H, OCH2CH3), 4.07-4.18 (m,
1
100 instrument at 400 and 100 for H NMR, 100 MHz for 13C
NMR, and 162 MHz for 31P NMR in CDCl3 solution, using TMS
as an internal standard. Melting points were recorded on an
electrothermal type 9100. Elemental analysis was performed on a
Thermo Finnigan Flash EAmicroanalyzer. The mass spectra were
recorded on a 5973 Network Mass Selective Detector.
1
2
2H, OCH2CH3), 4.60 (dd, JPH = 23.5 Hz, JPH = 8.4 Hz, 1H,
CHP), 4.78 (t, J = 8.4 Hz, 1H, NH), 6.55 (dd, 1J = 8.0 Hz, 2J = 2.4
Hz, 1H, Ar-H), 6.63 (d, J = 8.8 Hz, 2H, Ar-H), 6.70 (s, 1H), 6.80
(d, J = 8.8 Hz, 1H, Ar-H), 6.95 (t, J = 8.2 Hz, 1H, Ar-H), 7.26 (dd,
General procedure for the synthesis of a-aminophos-
phonates 4a-4p: A mixture of aldehyde (5 mmol), amine (5
mmol), and diethylphosphite (5 mmol) was stirred in a 10 ml
round bottom flask at 50-60 °C for the appropriate reaction time
(Table 1). The completion of the reaction was monitored by TLC.
After the completion of the reaction, resulting crude material was
recrystallized from EtOAC/n-Hexane (1:4) to afford the pure
a-aminophosphonates.
2
1J = 8.8 Hz, J = 2.4 Hz, 2H, Ar-H), 13CNMR (100.64 MHz,
CDCl3): d 12.5, 16.2 (d, 3JPC = 5.6 Hz), 16.4 (d, 3JPC = 5.6 Hz),
44.2, 55.3 (d, 1JPC = 153.4 Hz), 63.0 (d, 2JPC = 7.0 Hz), 63.3 (d,
2JPC = 6.9 Hz), 111.8, 112.4, 116.5, 120.8, 120.9, 123.0, 128.7 (d,
2JPC = 5.2 Hz), 130.3, 147.6, 148.0 (d, 3JPC = 14.3 Hz). 31P (162.03
MHz, CDCl3): d 22.97, m/z (ESI) 470 [20%, M+], 472 [5%,
M++2]. Anal. Calc. for C21H30BrN2O3P: C, 53.74; H, 6.44; N,
5.97. Found: C, 53.68; H, 6.36; N, 5.65.
Spectral data of the prepared compounds
Diethyl(((4-chlorophenyl) amino) (4-(diethylamino)
phenyl)methyl) phosphonate (4a): Yield 96%; m.p = 120-121
°C; IR (KBr, cm-1) u: 3297 (NH), 3048, 2978, 1613, 1598, 1521,
Diethyl (((4-(diethylamino)phenyl) (4-tolylamino) me-
thyl) phosphonate (4d): Yield 92%; m.p = 100-101 °C; IR (KBr,
cm-1) u: 3295 (NH), 3018, 2982, 1611, 1603, 1524, 1497, 1237
(P=O), 1060 (P-OEt); 1H NMR (100 MHz, CDCl3): d, 1.10-1.19
(m, 6H, OCH2CH3, m, 6H, NCH2CH3), 2.18 (s, 3H, CH3Ar), 3.30
(q, J = 8.0 Hz, 4H, NCH2CH3), 3.50-4.20 (m, 4H, OCH2CH3),
4.50 (d, J = 22.0 Hz, 1H, CHP), 4.55 (br, 1H, NH), 6.50-7.30 (m,
8H Ar-H). 31P (162.03 MHz, CDCl3): = 21.36. m/z (ESI) 404
[70%, M+]. Anal. Calc. for C22H33N2O3P: C, 65.33; H, 8.22; N,
6.93. Found: C, 65.25; H, 8.15; N, 6.88.
1
1492, 1232 (P=O), 1050 (P-OEt), 578; H NMR (100 MHz,
CDCl3) d: 1.00-1.40 (m, 6H, OCH2CH3, 6H, NCH2CH3), 3.33 (q,
J = 8.0 Hz, 4H, NCH2CH3), 3.78-4.07 (m, 4H, OCH2CH3), 4.60
(dd, 1JPH = 24.2 Hz, 2JPH = 7.1 Hz, 1H, CHP), 4.70 (br, 1H, NH),
6.40-6.70 (m, 4H, Ar-H), 7.00-7.30 (m, 4H, Ar-H), 31P (162.03
MHz, CDCl3): d 20.88. m/z (ESI) 424 [75%, M+], 426 [25%,
M++2]. Anal. Calc. for C21H30ClN2O3P: C, 59.36; H, 7.12; N,
6.59. Found: C, 59.30; H, 7.10; N, 6.56.
Diethyl (((4-bromophenyl)amino) (4-(diethylamino)
phenyl) methyl) phosphonate (4b): Yield 95%; m.p = 123-124
°C; IR (KBr, cm-1) u: 3294 (NH), 3018, 2972, 1613, 1592, 1524,
1497, 1232 (P=O), 1047 (P-OEt); 1H NMR (400 MHz, CDCl3) d:
1.13 (t, J = 7.2 Hz, 6H, NCH2CH3), 1.16 (t, J = 8.0 Hz, 3H,
OCH2CH3), 1.31 (t, J = 7.0 Hz, 3H, OCH2CH3), 3.33 (q, J = 7.0
Diethyl (((4-(diethylamino)phenyl) (3-tolylamino) me-
thyl) phosphonate (4e): Yield 90%; m.p = 140-141 °C; (KBr,
cm-1) u: 3295 NH, 3018, 2982, 1611, 1603, 1524, 1497, 1237
1
(P=O), 1060 (P-OEt) cm-1; H NMR (400 MHz,CDCl3): 1.13-
1.18 (m, 3H, OCH2CH3, 6H, NCH2CH3 ), 1.30 (t, J = 7.2 Hz, 3H,
OCH2CH3), 2.25 (s, 3H, CH3Ar), 3.33 (q, J = 8.0 Hz, 4H,
J. Chin. Chem. Soc. 2015, 62, 1087-1096
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NCH2CH3), 3.69–3.77 (m, 1H, OCH2CH3), 3.93-4.02 (m, 1H,
OCH2CH3), 4.08-4.20 (m, 2H, OCH2CH3), 4.66 (d, JPH = 23.3 Hz,
1H, CHP), 4.67 (br, 1H, NH), 6.45 (d, J = 8.0 Hz, 1H, Ar-H), 6.51
(s, 1H), 6.53 (t, J = 7.2 Hz, 1H, Ar-H), 6.65 (d, J = 8.0 Hz, 2H,
Ar-H), 7.02 (t, J = 7.6 Hz, 1H, Ar-H), 7.30 (d, J = 7.2 Hz, 2H,
Ar-H). 13CNMR (100.64 MHz, CDCl3): d 12.5, 16.3 (d, 3JPC = 6.0
Hz), 16.5 (d, 3JPC = 6.0 Hz), 21.6, 44.3, 55.2 (d, 1JPC = 153.5 Hz),
63.0 (d, 2JPC = 17.2 Hz), 63.1, 110.0, 111.8, 114.8, 119.0, 121.8,
128.0 (d, 2JPC = 6.1 Hz), 129.0, 138.8, 146.7 (d, 3JPC = 16.2 Hz),
147.5. 31P (162.03 MHz, CDCl3): d 23.58, m/z (ESI) 404 [45%,
M+]. Anal. Calc. for C22H33N2O3P: C, 65.33; H, 8.22; N, 6.93.
Found: C, 65.02; H, 8.10; N, 6.82.
Diethyl (((4-chlorophenyl)amino) (4-(dimethylamino)
phenyl) methyl) phosphon (4i): Yield 95%; m.p = 130-131 °C;45
IR (KBr, cm-1) u: 3293 (NH), 2982, 1612, 1597, 1525, 1492, 1230
(P=O), 1062 (P-OEt); 1H NMR (100 MHz, CDCl3): d 1.15 (t, J =
7.8 Hz, 3H, OCH2CH3), 1.31 (t, J = 7.8 Hz, 3H, OCH2CH3), 2.92
1
(s, 6H, NCH3), 3.50-4.20 (m, 4H, OCH2CH3), 4.60 (dd, JPH
=
24.0 Hz, 2JPH = 7.1 Hz, 1H, CHP), 4.7 (br, 1H, NH), 6.55 (d, J =
8.4 Hz, 2H, Ar-H), 6.70 (d, J = 8.2 Hz, 2H, Ar-H), 7.05 (d, J = 8.4
Hz, 2H, Ar-H), 7.30 (d, J = 8.2 Hz, 2H, Ar-H); m/z (ESI) 396
[15%, M+], 398 [10%, M++2]. Anal. Calc. for C19H26ClN2O3P: C,
57.50; H, 6.60; N, 7.06. Found: C, 57.01; H, 6.25; N, 6.78.
Diethyl (((4-bromophenyl) amino) (4-(dimethylamino)
phenyl)methyl)phosphonate (4j): Yield 96%; m.p = 135-136
°C; IR (KBr, cm-1): 3294 (NH), 2982, 1613, 1592, 1522, 1488,
1231 (P=O), 1063 (P-OEt); 1H NMR (400 MHz, CDCl3): d 1.15
(t, J = 7.2 Hz, 3H, OCH2CH3), 1.31 (t, J = 7.2 Hz, 3H, OCH2CH3),
2.94 (s, 6H, NCH3), 3.65–3.73 (m, 1H, OCH2CH3), 3.90-4.01 (m,
1H, OCH2CH3), 4.07-4.18 (m, 2H, OCH2CH3), 4.62 (d, JPH = 22.4
Hz, 1H, CHP), 4.81 (br, 1H, NH), 6.50 (dd, 1J = 8.8 Hz, 2J = 2.2
Hz, 2H, Ar-H), 6.70 (d, J = 8.4 Hz, 2H, Ar-H), 7.18 (d, J = 8.8 Hz,
2H, Ar-H), 7.30 (d, 1J = 8.4 Hz, 2J = 2.4 Hz, 2H, Ar-H); 13CNMR
(100.64, CDCl3): d 16.3 (d, 3JPC =6.3 Hz), 16.5 (d, 3JPC= 6.2 Hz),
40.5, 55.3 (d, 1JPC = 152.1 Hz), 63.1 (d, 2JPC = 7.0 Hz), 63.4 (d,
2JPC = 7.0 Hz), 109.9, 112.5, 115.5, 122.3, 128.6 (d, 2JPC = 5.0 Hz),
Diethyl ((4-(diethylamino)phenyl) (phenylamino) me-
thyl) phosphonate (4f): Yield 90%; m.p = 101-102 °C; IR (KBr,
cm-1) u: 3301 (NH), 3022, 2973, 1611, 1603, 1524, 1497, 1232
1
(P=O), 1061 (P-OEt); H NMR (100 MHz,CDCl3): d 1.01-1.40
(m, 6H, OCH2CH3, 6H, NCH2CH3), 3.23 (q, J = 8.0 Hz, 4H,
NCH2CH3), 3.71-4.01 (m, 4H, OCH2CH3), 4.30 (dd, 1JPH = 23.0
Hz, 2JPH = 7.2 Hz, 1H, CHP), 4.50 (br, 1H, NH), 6.60-7.30 (m, 9H,
Ar-H). m/z (ESI) 390 [55%, M+]. Anal. Calc. for C21H31N2O3P: C,
64.60; H, 8.00; N, 7.17. Found: C, 64.20; H, 7.74; N, 7.10.
Diethyl ((4-(diethylamino)phenyl)((4-nitrophenyl) amino)
methyl) phosphonate (4g): Yield 85%; m.p = 140-141 °C; IR
(KBr, cm-1) u: 3269 (NH), 3040, 2972, 1597, 1520, 1505, 1481,
1231 (P=O), 1051 (P-OEt), 574; 1H NMR (100 MHz, CDCl3): d
3
131.8, 145.6 (d, JPC = 15.2 Hz), 150.25. 31P (162.03 MHz,
1.00-1.40 (m, 6H, OCH2CH3, 6H, NCH2CH3), 3.43 (q, J = 8.1 Hz,
CDCl3): d 23.01. m/z (ESI) 440 [40%, M+], 442 [35%, M++2].
Anal. Calc. for C19H26BrN2O3P: C, 51.71; H, 5.94; N, 6.35.
Found: C, 51.50; H, 5.80; N, 6.6.21.
1
4H, NCH2CH3), 3.50-4.20 (m, 4H, OCH2CH3), 4.70 (dd, JPH
=
24.0 Hz, 2JPH = 7.5 Hz, 1H, CHP), 5.75 (br, 1H, NH), 6.60 (d, J =
8.0 Hz, 2H, Ar-H), 7.10-7.30 (m, 4H, Ar-H), 8.01 (d, J = 8.0 Hz,
2H, Ar-H); m/z (ESI) 435 [45%, M+]. Anal. Calc. for
C21H30N3O5P: C, 57.92; H, 6.94; N, 9.65. Found: C, 57.24; H,
6.75; N, 9.42.
Diethyl (((3-bromophenyl) amino) (4-(dimethylamino)
phenyl) methyl)phosphonatee (4k): Yield 92%; m.p = 110-111
°C; IR (KBr, cm-1): 3294 (NH), 3018, 2974, 1612, 1594, 1523,
1479, 1235 (P=O), 1057 (P-OEt); 1H NMR (100 MHz,CDCl3): d
1.15-1.30 (m, 6H OCH2CH3), 2.88 (s, 6H, NCH3), 3.60-4.21 (m,
Diethyl ((4-(diethylamino)phenyl) ((4-methoxyphenyl)
amino) methyl) phosphonate (4h): Yield 95%; m.p = 120–121
°C; IR(KBr, cm-1): 3299 (NH), 3018, 2971, 1611, 1520, 1510,
1234 (P=O), 1031 (P-OEt); 1H NMR (400 MHz, CDCl3): d
1.10-1.30 (m, 6H, OCH2CH3, 6H, NCH2CH3), 3.31 (q, J = 8.0 Hz,
4H, NCH2CH3), 3.69 (s, 3H, OCH3), 3.65-3.80 (m, 1H,
OCH2CH3), 3.93-3.97 (m, 1H, OCH2CH3), 4.08-4.14 (m, 2H,
OCH2CH3), 4.36 (b, 1H, NH), 4.57 (dd, 1JPH = 23.0 Hz, 2JPH = 7.2
Hz, 1H, CHP), 6.57-6.70 (m, 6H, Ar-H), 7.24-7.26 (m, 2H, Ar-H),
13CNMR (100.62, CDCl3): d 12.5, 16.2 (d, 3JPC = 6.0 Hz), 16.5 (d,
3JPC = 6.0 Hz), 44.3, 55.6, 56.2 (d, 1JPC = 152.5 Hz), 63.0, 63.1,
111.8, 114.7, 115.3, 121.9, 128.8 (d, 2JPC = 5.0 Hz), 140.9 (d, 3JPC
= 1.5 Hz), 147.5, 152.5. 31P (161.99 MHz, CDCl3): d 23.99 ppm,.
m/z (ESI) 420 [30%, M+]. Anal. Calc. for C22H33N2O4P: C, 62.84;
H, 7.91; N, 6.66. Found: C, 62.43; H, 7.68; N, 6.60.
1
2
4H, OCH2CH3), 4.32 (dd, JPH = 23.0 Hz, JPH = 7.0 Hz, 1H,
CHP), 4.7 (br, 1H, NH), 6.5-7.30 (m, 8H, Ar-H). 31P (162.03
MHz, CDCl3): d 23.70. m/z (ESI) 440 [30%, M+], 442 [28%,
M++2]. Anal. Calc. for C19H26BrN2O3P: C, 51.71; H, 5.94; N,
6.35. Found: C, 51.50; H, 5.90; N, 6.24.
Diethyl ((4-tolylamino)(4-(dimethylamino) phenyl) me-
thyl) phosphonate (4l): Yield 92%; m.p = 102-103 °C;2 IR (KBr,
cm-1) u: 3295 (NH), 3018, 2982, 1611, 1603, 1524, 1497, 1237
(P=O), 1060 (P-OEt), 1H NMR (100 MHz, CDCl3) d: 1.13-1.45
(m, 6H, OCH2CH3), 2.20 (s, 3H, CH3Ar), 2.70 (s, 6H, NCH3),
3.60-4.22 (m, 4H, OCH2CH3), 4.50-4.65 (m, 1H, CHP), 4.75 (br,
1H, NH), 6.58-7.53 (m, 8H, Ar); MS (m/z) 376 [20%, M+]. Anal.
Calc. for C20H29N2O3P: C, 63.81; H, 7.77; N, 7.44. Found: C,
63.75; H, 7.70; N, 7.26.
1094
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© 2015 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim J. Chin. Chem. Soc. 2015, 62, 1087-1096

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Synthesis of Novel a-Aminophosphonates
Diethyl ((3-tolylamino)(4-(dimethylamino) phenyl) me-
thyl) phosphonate (4m): Yield 95%; m.p = 120-121 °C; IR (KBr,
cm-1): 3300 (NH), 3035, 2981, 1607, 1600, 1524, 1489, 1236
(P=O), 1052 (P-OEt); 1H NMR (100 MHz, CDCl3): d 1.10-1.30
(m, 6H, OCH2CH3), 2.28 (s, 3H, CH3Ar), 2.91 (s, 6H, NCH3),
3.56-4.30 (m, 4H, OCH2CH3), 4.50 (d, J = 21.4, 1H, CHP), 4.60
(br, 1H, NH), 6.42-7.48 (m, 8H, Ar). 31P (162.03 MHz, CDCl3): d
23.36. m/z (ESI) 376 [45%, M+]. Anal. Calc. for C20H29N2O3P: C,
63.81; H, 7.77; N, 7.44. Found: C, 63.68; H, 7.36; N, 7.14.
Diethyl ((4-(dimethylamino) phenyl) (phenylamino)
methyl) phosphonate (4n): Yield 90%; m.p = 112-113 °C;54 IR
(KBr, cm-1) u: 3293 (NH), 3031, 2982, 1602, 1525, 1497, 1236
(P=O), 1052 (P-OEt); 1H NMR (100 MHz, CDCl3): d 1.1-1.4 (m,
6H, OCH2CH3), 2.85 (s, 6H, NCH3), 3.60-4.20 (m, 4H,
OCH2CH3), 4.30 (d, JPH = 23.0 Hz, 1H, CHP), 4.54 (br, 1H, NH),
6.60-7.40 (m, 9H, Ar-H). m/z (ESI) 362 [80%, M+] Anal. Calc. for
C19H27N2O3P: C, 62.97; H, 7.51; N, 7.73. Found: C, 62.21; H,
7.45; N, 7.63.
Hz), 115.0, 122.9, 127.2 (d, 2JPC = 3.0 Hz), 128.9, 144.9, 145.8,
159.4 (d, 3JPC = 15.3 Hz) ppm. 31P (162.5 MHz, CDCl3): d 23.01
m/z (ESI) 393 [90%, M+]. Anal. Calc. for C20H29N2O4P C, 61.21;
H, 7.45; N, 7.14. found: C, 60.85; H, 7.10; N, 7.05.
ACKNOWLEDGEMENTS
We are grateful to Ferdowsi University of Mashhad
Research Council for their financial support of this work
(GN: 3/25468).
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