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

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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,^aHossein Eshghi,^a* Mohammad Rahimizadeh,^aMehdi Bakavoli,^aMaryam M. Matin,^b

Minoo Hosseinymehr,^bHadi Amiri Rudbari^cand Giuseppe Bruno^d

^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,³¹FeCl₃,¹TiO₂,³²NaHSO₄-SiO₂,³³Nano

Fe₃O₄,³⁴g-Fe₂O₃@SiO₂-PA,³⁵DHAA-Fe₃O₄,³⁶IRMOF-3

nano,³⁷Fe/SWCNTs,³⁸ZrOCl₂.8H₂O,³⁹TiCl₄,⁴⁰VCl₃,⁴¹

and ethyl ammonium nitrate.⁴²However, 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,^1,2enzymes inhibitors,^3,4haptens of catalytic anti-

bodies,^5-7pharmacologic agents,^6,7antifungal activity,⁸in-

secticides,⁹plant growth regulators,¹⁰and 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,²⁰molecular iodine,²¹Xanthan Sulfuric Acid,²²

DTP/SiO₂,²³succinic acid,²⁴Phenylphosphonic acid,²⁵

SnCl₂,²⁶SiO₂-AlCl₃,²⁷InCl₃,²⁸Mg(ClO₄)₂,²⁹M(OTf)₃,³⁰

RESULTS AND DISCUSSION

We previously reported a catalyst-free method for the

three-component Mannich reaction.⁴⁸Now 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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Eshghi et al.

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-

nate^a

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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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 C_aatom, 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.⁵⁰There 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).^49-51According 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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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

NA^b

235 ± 2.3

46.5 ± 4.3

201 ± 4.5

45 ± 4.2

145 ± 4.2

NA^b

232 ± 4.8

48 ± 4.6

204 ± 4.8

42 ± 4.4

142 ± 4.3

NA^b

Fig. 2. A pair of hydrogen bonds in a Centro symmet-

ric dimer of 4j.

200 ± 4.3

NA^b

4i

4j

4k

4l

4m

4n

4o

4p

docetaxel

210 ± 2.5

180 ± 2.3

246 ± 4.5

NA^b

212 ± 4.4

182 ± 2.7

240 ± 2.4

NA^b

246 ± 2.4

NA^b

245 ± 1.2

NA^b

40 ± 4.4

215 ± 4.2

191 ± 4.9

239 ± 4.7

NA^b

Biological activity

The in vitro cytotoxicity of these compounds was

evaluated against DU145 prostate cancer cells by the MTT

method⁵²The 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 IC₅₀using Graph Pad Prism V.3

software.

³ 250

NA^b

³ 250

NA^b

44 ± 4.5

30 ± 4.3

^aArithmetic 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

^bNA: 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.⁵³In this study, the cytotoxic effects of docetaxel

were evaluated on DU145 cells and the data are shown in

(Table 2). Its IC₅₀values 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 density¹⁸of 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% CO₂in 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 ´ 10³cells/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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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, J_PH

=

23.0 Hz, ²J_PH= 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, ³J_PC= 5.6 Hz), 16.4 (d, ³J_PC= 5.6

Hz), 44.2, 55.3 (d, ¹J_PC= 152.9 Hz), 63.0 (d, ²J_PC= 7.0 Hz), 63.3

2

(d, J_PC= 6.9 Hz), 109.8, 111.8, 115.5, 120.9, 128.7, 131.8, (d,

²J_PC= 5.0 Hz), 145.6 (d, ³J_PC= 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 CDCl₃solution, 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, J_PH= 23.5 Hz, J_PH= 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, ³J_PC= 5.6 Hz), 16.4 (d, ³J_PC= 5.6 Hz),

44.2, 55.3 (d, ¹J_PC= 153.4 Hz), 63.0 (d, ²J_PC= 7.0 Hz), 63.3 (d,

²J_PC= 6.9 Hz), 111.8, 112.4, 116.5, 120.8, 120.9, 123.0, 128.7 (d,

²J_PC= 5.2 Hz), 130.3, 147.6, 148.0 (d, ³J_PC= 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, ¹J_PH= 24.2 Hz, ²J_PH= 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,

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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, J_PH= 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, ³J_PC= 6.0

Hz), 16.5 (d, ³J_PC= 6.0 Hz), 21.6, 44.3, 55.2 (d, ¹J_PC= 153.5 Hz),

63.0 (d, ²J_PC= 17.2 Hz), 63.1, 110.0, 111.8, 114.8, 119.0, 121.8,

128.0 (d, ²J_PC= 6.1 Hz), 129.0, 138.8, 146.7 (d, ³J_PC= 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, J_PH

=

24.0 Hz, ²J_PH= 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, J_PH= 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, ³J_PC=6.3 Hz), 16.5 (d, ³J_PC= 6.2 Hz),

40.5, 55.3 (d, ¹J_PC= 152.1 Hz), 63.1 (d, ²J_PC= 7.0 Hz), 63.4 (d,

²J_PC= 7.0 Hz), 109.9, 112.5, 115.5, 122.3, 128.6 (d, ²J_PC= 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, ¹J_PH= 23.0

Hz, ²J_PH= 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, J_PC= 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, J_PH

=

24.0 Hz, ²J_PH= 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, ¹J_PH= 23.0 Hz, ²J_PH= 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, ³J_PC= 6.0 Hz), 16.5 (d,

³J_PC= 6.0 Hz), 44.3, 55.6, 56.2 (d, ¹J_PC= 152.5 Hz), 63.0, 63.1,

111.8, 114.7, 115.3, 121.9, 128.8 (d, ²J_PC= 5.0 Hz), 140.9 (d, ³J_PC

= 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, J_PH= 23.0 Hz, J_PH= 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;²IR (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

www.jccs.wiley-vch.de

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;⁵⁴IR

(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, J_PH= 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, ²J_PC= 3.0 Hz), 128.9, 144.9, 145.8,

159.4 (d, ³J_PC= 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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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

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