Synthesis of Biologically Potent α-Aminophosphonates Derivatives by Nano-Catalyst

Introduction

α-Aminophosphonate is a valuable part of organo-phosphorus compounds due to their similarity in structure and properties to α-amino acids¹. it plays  an important role in several field including organic synthesis and various potential applications². Nowadays researchers have been attentively move towards  pesticide, biochemistryand medicinal chemistry last few years because they  show  biological activity. Some α-aminophosphonate show activity against tumor³,  activity against microbes⁴ , they inhibits the enzyme⁵, they act an antiviral agent⁶,  some of the α-aminophosphonates containing alkoxyethyl moieties shows antiviral bioactivity⁷ .The Kabachnik-Field reaction and  the Pudovic reaction are the two major routs to synthesizing the biologically potent α-Aminophosphonates. In the first reaction (Phospha-Manich) it contains three component condensation including aldehyde or ketone ,a mine and diethyl  phosphate^8-9. In the second, it contains imines with >P(O)H reagent¹⁰. The classical version of the “Phospha-Manich” reaction was discovered by independently Kabachnik and fields more than sixty years ago^11-12.

The researchers, while synthesizing of α-aminophosphonates used catalyst i.e. efficient Amberlight IRC-748¹³. An Extremely Efficient Three-Component (KFR) using oxidizing agent  Magnesium Perchlorate¹⁴,Zirconium(IV) compounds¹⁵,The Efficient catalyst NbCl5¹⁶, The efficient anthem sulphuric acid¹⁷, Promiscuous Lipase catalyzed (NiSO4.6H2O)a new P-C bond formation in (MCR)[18]Tin(II) compound  as catalyst for (KFR)¹⁹.

Thederivatives of α-Aminophosphonates synthesized by Multicomponent condensation through Kabachnik-Field Reaction¹², are widely explained with a variety of catalysts. Now we have recently reporte the nano (PAni-Mn) catalyst as a novel catalyst used to form α-Aminophosphonates. The (PAni-Mn) Nano catalyst was used for the first time in Kabachnik-Field Reaction for α-Aminophosphonates synthesis. During the last decade, Polyaniline had great importance in the catalytic field^20-21. The doping of the polyanilinewith metal increases the catalytical activity²². The Fe-polyaniline composite Nano-fiber catalystfor chemo selective hydrolysis ofoxime²³. In proposed work first prepares polyaniline, doping should be done with the help of MnCl₂. The synthesized Nano material i.e the nano catalyst (PAni-Mn) is utilized for preparation of α-aminophosphonates derivatives.KFR involes condensation of primary or secondary amines,carbonyl compounds i.e. aldehyde or ketonesand dialkyl  phosphite²⁴. The Nano catalyst gives a high yield, short reaction time, it provides high surface area, increased catalytical activity. The synthesized Nano –catalyst was fully characterized by X-ray Diffraction, HR-TEM, FEG-SEM, FTIR.

Materials and methods

Materials

All chemicals are used in these experiments, which are supplied by Sigma Aldrich with high purity.

 Synthesis of polyaniline

The chemical oxidation methods were used for PANI-ES synthesis lower than (5 ºC ).  mL, Aniline (mL)  was dissolved in Hydrochloric acid(70 mL, 1.5 M) his mixture is kept in an ice bath to maintain the temperature below 4-5 ºC.  The 10gm Oxidizing agent Ammonium Per Sulfate (APS) was dissolved in deionized water. The solution of APS was added drop by drop into monomer solution. This mixture was stirred with a magnetic stirrer up to 4-5 hours²⁵. The polymerization process is carried out, at the end of the polymerization reaction, the green color Polyaniline was formed, washed 2-3 times with D.W. and methanol.   Finally, the dark-green composite powder is dried at 70^oC in a hot air oven, for 10-12 hours. The final product was grounded to form a green powder (Figure 1 ).

Figure 1: Structure of Polyaniline. Click here to View figure

Preparation of Polyaniline Nano-catalyst

After formation of polyaniline Emeraldine salt (ES), the accurate amount of solution of manganese chloride MnCl₂ slowly and carefully dissolved in polyaniline. The polyaniline manganese chloride solution was kept for stirring with the help of a round bottom flask and Magnetic stirrer (700 RPM) for about 5 hours. After filtration, the product washed 3 times with deionized water and three times with ethanol. The prepared nano catalyst was kept in a hot air oven for 6 hours at 70-80⁰C. In this method the nano particles of Mn was uniformly distributed in polyaniline^26-27. there is formation of a nano catalyst having a dark  green color (Figure 2)

Figure 2: Freshly PAni-Mn Nano catalyst prepared. Click here to View figure

Result and Discussion

Polyaniline(X-RD) Analysis

The X-RD technique is used to determine the crystalline nature of polyaniline. ThePANi-ES gives three different peaks at room temperature i.e. 20.1, 25.3, 26.7⁰ C, respectively as shown in figure-2. Polymer is semi-crystalline in nature as the pattern shows sharp peaks due to the presence of Benzenoid and qunonoid groups in the polyaniline²⁸.

The sharp peak is observed in the XRD spectrum 2θ=25.255⁰  Thei nterplanar distance value obtained is 3.35A⁰. Hence the average crystallite size is calculated on the basis of the Debye Scherer Equation.  (D= kλ /β cos θ) in this equation 1) D= average size of crystallite 2) k = 0.89 (Shape of factor),λ= (1.54A⁰) , β = full width at half maximum ; θ = angle of diffraction²⁹.

Table 1: Polyaniline data of XRD

Pos [ 02Th]	Height t [cts]	FWHM [02Th ]	d- Spacing [A0]	Rel. Int [%]
25.255	17.32	1	3.53544	100.00

Figure 3: XRD Analysis of Polyaniline (ES). Click here to View figure

The average crystallite size value obtained is 1.387 nm on the basis of XRD data given in table 1.

SEM Characterization

The main objective of scanning electron microscopy is to determine morphological features and surface characteristics of the compounds. The instruments used JEOL JSM-7600F FEG-SEM.  Morphology of polyaniline (ES) shows fibrous in nature particle size is around 1μm,100μm.This shows that the material is in good shape having high surface area, nano fibre which is used for further application. at high temperature polyaniline (ES), tends to formnano-rod like structure. The factors such as polymerization process, polymerization rate, growth of polymers and solvent interfacial tension are also involved in the formation of nano rods³⁰.

Figure 4: SEM-Polyaniline(ES) 1μm. Click here to View figure

Figure 5: SEM-PANI(ES) 100 μm. Click here to View figure

Figure 6: SEM-Pani(Es) 1μm Click here to View figure

TEM (300kV) Characterization

The TEM300kV.can be used to study electron beams to image a Nano  particle and generate highly magnified images. The Nano structure of the polyaniline is shown in the following micrographs on the basis of TEM analysis, the particle size of Polyaniline is very small, i.e.1um, 200nm, 50nm. It is spherical in shapes, having the rough surface.

Figure 7: TEM Images of PAni (1μm) Click here to View figure

Figure 8: TEM Images of PAni (200nm). Click here to View figure

Figure 9: TEM Images of PAni 50nm. Click here to View figure

Fourier- transforms infrared spectroscopy (FTIR)

The prepared polyaniline was identified by FT-IR spectroscopy. The main characteristics peaks observed as 377, 3464, 3232, 2923, 2852, 1663, 1558, 1469, 1299, 1240, 1113, 1006, 878, 797, 679, 562, and 504 cm^-1sample was run in the wavelength 4000-900cm^-1. The FT-IR spectra of synthesized pure polyaniline (ES) is presented in Figure 9. In a spectrum, the characteristic   band observed at 3464-3727cm^-1 as a result of nitrogen-hydrogen stretching.  The polymers peak observed on 3232, 2923, 2852cm^-1as a result of asymmetric, symmetric carbon-hydrogen vibration. The  C=C of aromatic ring Absorption spectra observed on 1663 cm^{-1 31}. absorption spectra observed on sharp 1557cm^-1 is the result of C-H stretching in an aromatic compound. The IR spectrum band observed at 1468.59 cm^-1corresponds to C=N stretching in ring aromatic compound. 1240-1299 cm^-1. the polymer absorption band of C-N stretching On the basis of this, it confirm the presence of amine group³².

An FT-IR spectrum valued at 1113 cm^-1 reveals the C-H bending vibrations. The absorption band lies below 504, 562, 679, 798, 878, 1006, 1044 cm-1show these spectral values showing the benzene ring being substituted by another group Consequently it shows  polymerization³³. The coupling of the phenyl nuclei within the amine group is mainly attached to Para position. On the basis of above FT-IR analysis data confirm that the prepared compound is polyaniline.

Figure 10: FT-IR spectrum of polyaniline(ES). Click here to View figure

Preparation of α-Aminophosphonates using Nano-Catalyst

α-Aminophosphonate derivates are synthesized through Kabachnik-Fields reaction. Equimolar quantity of aldehyde (10 mmol),  different aromatic amine (10mmol), diethyl phosphate (10mmol).Using a catalytic quantity of (PAni-Mn) nano catalyst. In a solvent free environment, they were agitated at room temperature³⁴. The completion of reaction as indicated  by TLC^35-36. The reaction mixture was extracted with ethyl acetate and quenched with water (10 ml). The formation of pure α-aminophosphonate follows the purification of the compound in silica gel.

Result and Discussion

Following α-Aminophosphonate derivatives were prepared.

Diethyl-3-chlorophenylamino-4-hydroxy-3-methoxy-5-nitrophenyl methylphosphonates.

M.F. C₁₈H₂₂ClN₂O₇P M.W= 444, dark brown color m. p. = 177-179^°C, yield=88%

Scheme 1 Click here to View scheme

¹HNMR(300MHz, DMSO-d₆)ẟ_H; 10.3 (s, 1H,-OH), 8.90-6.58 (m, 6H, Ar-H),5.02-xx (m, 1H,N-H), 4.05-xx (m, 1H,P-CH), 3.81 (q ,4H, P-OCH2), 3.15 (s, 3H, -OCH3), and 1.12 (s, 3H, -OCH3) (t, H, -OCCH3). /1162 MHz, 32  M/Z = 444 and 446 with a 3:1 ratio for 31P-NMR³⁷.

Diethyl (4-methoxyphenyl)-N -(Phenyl amino) methylphosphonate

M.F. C₁₈H₂₄NO₄P M.W= 349, dark yellow color m. p. = 57-59^°C, yield=92%

Scheme 2 Click here to View scheme

¹HNMR(300MHz, CDCl₃)ẟ_H; ẟ1.01-1.07(m,3H), 1.17-1.21(m, 3H), 3.71 (s,3H) 3.62-3.64, 3.84-3.88, 4.04-xx(m, 4H), 4.57-4.68(m, 2H), 6.51-6.62(m, 3H), 6.76-6.80(m, 2H) and 7.0-xx(m,2H), 7.30-7.32(m, 2H). 31P-NMR (16.9 MHz, DMSO-d6) With a 3:1 ratio, 30.6 M/Z equals 444 and 446³⁸.

Diethyl (2-chloro phenyl amino) nitrophenyl methyl (4-hydroxy-3-methoxy) phosphonate.

M.F. C₁₈H₂₂ClN₂O₇P  M.W= 408, brown color m. p. = 174-177^°C, yield=87%

Scheme 3 Click here to View scheme

¹HNMR(300MHz, DMSO-d₆)ẟ_H: 8.20(s, 1H, ArH), 7.28(d, 1H, J=6.5 Hz, ArH), 6.989d, 1h, J=6.5 Hz, ArH), 6.92(d, 2H, J=6.5Hz, ArH) 6.70(s, 1H, ArH), 4.80(d, 1H, J_CHPO=23.7 Hz, CHP) 4.02-4.12(m, 2H, OCH2CH3), 3.95-3.98(m, 1H, OCH₂CH₃), 3.90(s, 3H, OCH3) 3.70-3.75(m, 1H, OCH2CH3), 1.26(t, 3H, J=6.4 Hz, CH₃), 1.15(t, 3h, J=6.4 Hz, CH3) 31P –NMR (16.5 MHz, DMSO-d6, at 30.4M/Z= 440 and 442³⁹.

Diethyl(4-methoxy phenyl)-N- (4-chlorophenyl amino) methylphosphonates

M.F. C₁₈H₂₃ClNO₄P  M.W= 366, yellow color m. p. = 161-163^°C, yield=91%

Scheme 4 Click here to View scheme

¹HNMR(300MHz, DMSO-d₆)ẟ_H;  7.41(d, 2H, J=7.4Hz, Ar-H), 7.14((t, 2H, J=7.4 Hz, ArH,), 6.91(d, 2H, J=8.4 Hz, Ar H), 6.71(d, 2H, J=8.4 Hz, Ar-H), 6.71(t, 1H, J= 7.24, Hz, Ar-H), 6.62(d, 2H, J=8.1 Hz, Ar-H), 4.76 (s, 1H, NH), 4.75(d, 1H, J_CHPO=40.0. Hz, CHP), 4.12-4.18(m, 2H, OCH₂CH₃), 3.94-4.0 (m, 1H, OCH₂CH₃), 3.78(s, 3HOCH₃), 3.70-3.76(m, 1H, OCH₂CH₃), 1.30(t, 3H, J=7.2Hz, CH₃), 1.18(t, 3H, J= 7.2 Hz, CH₃).

     ³¹P-NMR (16.1 MHz, DMSO-d₆) ẟ30.1M/Z = 448 and 447 with 3:1 ratio⁴⁰.

Diethyl phenyl (phenyl amino) methyl phosphonate

M.F. C₁₇H₂₂NO₃P  M.W= 318, white color m. p. = 93-95^°C, yield=89%

¹HNMR(300MHz, CDCl₃)ẟ_H; 1.1(3H, JHH= 7.1Hz, t, OCH₂ CH₃); 1.3 (3H, JHH=7.1Hz, t, OCH₂ CH₃); 3.74-4.4 (m, 4H, OCH₂ CH₃); 5.1(s, 1H, NH); 4.8(1H, JHP=24.6 Hz, d, CHP); 5.1(m, 10H, Ar-H), 31P –NMR (16.3 MHz DMSO-d6) with 3:1 ratio.[41]

scheme 5 Click here to View scheme

Conclusion

Using the one-pot, three-component Kabachnik-field reaction, it was possible to synthesize novel derivatives of α-aminophosphonates. The use of different types of aldehyde, substituted aniline and dialkyl phosphate under solvent free condition using a novel nano-catalyst (PAni-Mn). The nano catalyst doped polyaniline with manganese (PAni-Mn) has greater efficiency, simple reaction condition, easy to handle and efficient. The Nano-catalyst was characterized by X-ray diffraction, HR-TEM, FEG-SEM, FTIR technique. All the prepared compounds were analyzed. It is worth mentioning that this catalyst is first used in the synthesis of α-aminophosphonates.

Application of work in future

It is important to reduce the cost of drugs due to easy synthesis. In future the nano catalyst is widely used a catalyst for high yield.

Acknowledgement

The SAIF IIT Bombay, SAIF COCCHI, and KERAL are gratefully acknowledged by the authors for providing analytical assessment facilities. The Research Center, Department of Chemistry, G.S. College Khamgaon, Dist-Buldana (MS) India, and Late Ku.Durga K. Banmeru Science College Lonar-Dist-Buldana-443302 (MS) India has both provided assistance to the authors.

Conflict of Interest

There is no conflict of interest.

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