Kabachnik – Fields synthesis of novel 2-oxoindolin methyl phosphonate derivatives using CAN .

The work reports ultrasound promoted facile synthesis of novel ten α-aminophosphonate derivatives coupled with indole-2,3-dione moiety, namely diethyl(substituted phenyl/heteryl)(2(2-oxoindolin 3ylidene)hydrazinyl)methylphosphonates derivatives 4(a-j).The derivatives 4(a-j) were synthesized through one-pot three component Kabachnik-Fields reaction, by stirring at room temperature in presence of Cerric Ammonium Nitrate (CAN) as a catalyst, to give the final compounds in better yields and in shorter reaction time. Isatin, chemically known as H-indole2,3-dione, and its derivatives possess a broad range of biological and pharmacological properties. Isatin is widely used as starting material for the synthesis of a broad range of heterocyclic compounds and as substrates for drug synthesis. The α-amino phosphonate derivatives constitute an important class of organophosphorus compounds on account of their versatile biological activity. The general low mammalian toxicity of these compounds made them attractive for use in agriculture and medicine. Considering the importance of the two pharmacophores, promoted us to club both the pharmacophores in a single molecule using green synthetic protocol. The structures of the ultrasound synthesized compounds were confirmed by spectral analysis like IR, H NMR, C NMR, P NMR and MS.


Introduction
The basic method for the preparation of α-aminophosphonates, valuable synthetic equivalents and biologically active substrates, involves the condensation of a primary or secondary amine, a carbonyl compound (aldehyde or ketone) and dialkylphosphite [1].List of various catalysts used for synthesis of various types α-aminophosphonates and the time (minutes) required for synthesis of α-aminophosphonates are shown in Table 1.
Among the synthetic routes towards α-aminophosphonates two main pathways exist.[2] a) Three-component reactions ( Kabachnik-Fields reaction): In this an aldehyde, an amine and di-or trialkylphosphite are reacted in a one-pot set-up.b) Pudovik reaction: In this dialkylphosphites are added to compound containing an iminobond.
α-aminophosphonates are among the most studied bioactive organo phosphorus derivatives and have been used as enzyme inhibitors [3], inhibitors of serine hydrolase [4], peptide mimics [5], antiviral [6], antibacterial [7], antifungal [8], anticancer [9], anti-HIV [10], antibiotics [11], herbicidal [12] etc. Indole possesses various medicinal properties like antibacterial, antifungal, anti-malarial, anticonvulsant and anti-inflammatory etc. [13].Isatin, chemically known as 1-H-indole-2,3dione, and its derivatives possess a broad range of biological and pharmacological properties and are widely used as starting materials for the synthesis of a broad range of heterocyclic compounds and as substrates for drug synthesis.It is also used for the inhibition of pro-apoptotic jurkat T cells.In terms of its mode of action, isatin itself is proposed to inhibit cancer cell proliferation via interaction with extracellular signal-related protein kinases (ERKs), thereby promoting apoptosis.These compounds inhibit cancer cell proliferation and tumor growth via interaction with a variety of intracellular targets such as DNA, telomerase, tubulin, P glycoprotein, protein kinases and phosphatases [14].Isatin-based hydrazones have been identified as inhibitors of the protein tyrosine phosphatase Shp2, which plays an important role in cell signaling, cell proliferation, differentiation and migration [15].The marketed anticancer drug Sunitinib [16] and Oratinib contains 2-oxoindolin-3-ylidene moiety where as Ilmofosin and Edelfosin contains phosphonate moiety and a recently marketed anticancer drug, Toceranib phosphate [17] contains 2-oxoindol-3-ylidene as well as phosphonates moiety.Considering the biological importance of 2-oxoindolin-3-ylidene and α-aminophosphonates prompted us to synthesize coupled derivatives containing isatin based hydrazone and α-aminophosphonates with the hope to get novel hybrid derivatives.The designing protocol for the target molecules is as shown in Fig. 1.

Fig.1: The designing protocol for target compounds
Most remarkable pathway to the synthesis of α-aminophosphonates is the Kabachnik-Fields reaction, the one pot three-component reaction of aromatic/heterocyclic aldehyde, amine and triethylphosphite, also known as Kabachnik-Fields reaction [18].The novel trends in carrying out this reaction are connected with the application of (i) microwave irradiation itself or in combination with catalyst [19], (ii) ionicliquids as solvents [20],(iii) use of appropriate dehydrating agents [21]and, probably most important, (iv) the use of catalysts, was achieved by using various catalyst like ZrOCl2.8H2O[22], YbCl3 [23], lanthanide triflates [24], Mg(ClO4)2 [25], LiClO4 [26] etc. Kabachnik-Fields reaction was promoted by using Cerric (IV) ammonium nitrate (CAN) as a catalyst because of its advantages like high solubility in organic solvent, ease of handling, and low toxicity [27].

Chemistry
Diethyl (substituted phenyl/heteryl)(2-(2-oxoindolin-3ylidene)hydrazinyl)methyl phosphonates derivatives 4(a-j) were synthesized by Green protocol as outlined in Scheme 1. 3hydrazonoindolin-2-one (1) was synthesized by reacting indole-2,3-dione (isatin) (1mmol) with hydrazine hydrate (1mmol) in the presence of glacial acetic acid as a catalyst by conventional method in methanol using molecular sieves and by ultrasonication method by replacing methanol with ethanol.Ultrasound method is better than the conventional method because, methanol being toxic solvent is replaced by benign solvent ethanol.The amount of solvent required is also less than that required for conventional method.Ultrasound assisted method gives better yield in 15-20 minutes against 3-4 hrs required for conventional method.α-Aminophosphonate derivatives 4(a-j) were synthesized by reacting 3-hydrazonoindolin-2-one

Chemistry
All the chemicals used for synthesis were of Merck, Sigma, Research lab, Qualigens make and Himedia.The FTIR spectra were obtained using JASCO FTIR-4000 and peaks were expressed in terms of wave number (cm -1 ).The 1 H NMR and 13 C NMR spectra of synthesized compounds were recorded on Bruker Avance II 400 NMR Spectrometer at 400 MHz Frequency in CDCl3 and using TMS as internal standard (chemical shift δ in ppm).The Mass spectra were scanned on Water's Micromass Q-Tof system.The 31 P NMR of compounds was recorded at δ 250 to δ 250 in CDCl3 and using Phosphoric acid (H3PO4) as external standard (chemical shift δ in ppm).Ultrasound synthesizer Vibra Cell VCX-500(Sonics, Newtown, CT, USA) with solid probe was used for synthesis of intermediates (1).

Procedures:
Step I:

Conclusion
Ultrasound synthesizer have become a promising alternative green tool for various chemical reactions due to their economic status like less time and electricity consumption by faster reaction.Intermediates (1) were synthesized by Green protocol such as by using ultrasound synthesizer, which gives the better yield in 15-20 minutes while conventional method requires 3-

( 1 )
, substituted/heteryl aldehydes 2(a-j) and triethylphosphite(3) via one pot synthetic step in presence of CAN as a catalyst.CAN activates the imine formation due to which addition of phosphite is facilitated to give a phosphonium intermediate.This phosphonium intermediate undergoes reaction with water to give the title compounds.CAN catalyst being water soluble can be easily removed after completion of reaction.The synthesized compounds were characterized and confirmed by FTIR, 1 H NMR, 13 C NMR, 31 P NMR, MS and elemental analyses.The purity of the synthesized compounds was checked by TLC and melting points were determined in open capillary tubes and are uncorrected.Physical constant data for diethyl (substituted phenyl/hetery)(2-(2-oxoindolin-3-ylidene)hydrazinyl) methyl phosphonates 4(a-j) is shown inTable 2.
ml of methanol was refluxed for 3-4 hr in presence of molecular sieves.• 1 /3Na2O•Al2O3•2SiO2• 9 /2H2O.[29]Since the 1990's, these molecular sieves have attracted considerable attention due to their potential use in catalysis, as they absorb water formed in the reaction and drive the reaction to completion.The separated crystals were filtered, washed with a little amount of methanol, dried and recrystallized with chloroform solvent(s), M.P. 284 °C, Yield 82%.B) Ultrasonication MethodEquimolar quantities of indole-2,3-dione (isatin) (1 mmol) and hydrazine hydrate (1mmol) in the presence of catalytic amount of glacial acetic acid in absolute ethanol (5 ml) was sonicated by keeping the reaction mixture in acoustic box containing Ultrasonic solid probe at 25-40°Cand at 25 amplitude for 15 -20 min.The completion of reaction was monitored by TLC.The reaction mixture was concentrated and cooled.The obtained solid was filtered and dried.The product was recrystallized from ethanol.3-Hydrazonoindolin-2-one, C8H7O1N3, MW: 161.13.Yield: 95%; melting point: 279-284°C.The melting point was uncorrected.

4
hrs.Final compounds 4(a-j) were synthesized through a one-pot three-component reaction process, a Kabachnik-Fields reaction in presence of CAN as a Green catalyst.Novel diethyl (substitutedphenyl/heteryl)(2-(2-oxoindolin-3ylidene)hydrazinyl)methylphosphonate derivatives 4(a-j) were synthesized at room temperature in facile one pot reaction using CAN as a green catalyst, which gives faster reaction at room temperature.CAN catalyst being water soluble can be easily removed after completion of reaction.The synthesized compounds were characterized by TLC, IR, NMR, and Mass spectrometry.