Ultrasound Assisted Synthesis of Diethyl ( 2-( 1-( morpholinomethyl )-2-Oxoindolin-3-ylidene ) hy drazinyl ) ( Substituted Phenyl / heteryl ) MethylphosphonateDerivatives †

This work reports ultrasound assisted synthesis diethyl (2-(1-(morpholinomethyl)-2-oxo indolin-3-ylidene)hydrazinyl) (substituted phenyl/heteryl) methylphosphonate 9(a–j) derivatives. The derivatives are synthesized using a green protocol. In the first step, 3-hydrazonoindolin-2-one is synthesized using ultrasound. In the second step, diethyl (substituted phenyl/heteryl)(2-(2-oxoindolin-3-ylidene)hydrazinyl) methylphosphonate 6(a–j) derivatives are synthesized using cerric ammonium nitrate as catalyst. In the third step, diethyl (2-(1-(morpholino methyl)-2-oxoindolin-3-ylidene)hydrazinyl) (substituted phenyl/heteryl) methylphosphonate 9(a–j) derivatives are synthesized using ultrasound. Isatin, chemically known as H-indole-2,3-dione, and its derivatives possess a broad range of biological and pharmacological properties. Isatin is widely used as a 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. Morpholine moiety has been found to be an eminent pharmacophore in medicinal chemistry. A number of molecules possessing morpholine moiety are clinically approved drugs. The importance of this ring is well understood by medicinal chemists, since they play a major role in molecular properties such as an electronic distribution, three dimensionality, scaffold flexibility/rigidity, lipophilicity or polarity and metabolic stability. Considering the importance of the three pharmacophores, this promoted us to club these pharmacophores together in a single molecule using a green synthetic protocol.The structures of the ultrasound synthesized compounds were confirmed by spectral analysis like IR, 1H NMR, 13C NMR, 31P NMR and MS.

On the other hand, morpholine moiety has been found to be an eminent pharmacophore in medicinal chemistry [13].A number of molecules possessing morpholine moiety are clinically approved drugs [13].The importance of this ring is well understood by medicinal chemists, since they play a major role in molecular properties, such as an electronic distribution, three dimensionality, scaffold flexibility/rigidity, lipophilicity or polarity and metabolic stability [14].
In view of these facts, we synthesized novel diethyl (2-(1-(morpholinomethyl)-2-oxoindolin-3ylidene)hydrazinyl) (substituted phenyl/heteryl) methylphosphonate9(a-j) derivatives under ultrasound irradiation using a green protocol.Ultrasound assisted techniques were reported to be more effective in terms of environment, reaction time, high yields, ease of work-up and isolation of products [15].
The amalgamation of two dissimilar bioactive pharmacophores made into a single molecule is a successful and frequently used approach in modern medicinal chemistry for the exploration of novel and highly active compounds which may have synergistic effects on biological properties [16].Hence, in the pursuit of developing a novel agent, the coupling of the three important pharmacophores i.e., indole-2-one, morpholine and α-aminophosphonate in a single molecule is designed by aiming at the identification of new molecules with enhanced biological activity.The synthesis of aforementionedconjugates could be possible by a pharmacophore hybrid approach of modern medicinal chemistry.The designed protocol for the synthesis of the target compounds is as shown in Figure 1.

Experimental
All the chemicals, unless otherwise specified, were purchased from commercial sources and were used without further purification.The major chemicals were purchased from Sigma Aldrich and Avralabs.The progress of the reactions was monitored by thin layer chromatography (TLC) analysis on Merck pre-coated silica gel 60 F254 aluminum sheets, visualized by UV light.The Ultrasound Sonicator (Sonics Vibra-cell, Model no.VCX 500) equipped with solid synthetic probe, 13 mm in tip diameter, operating at 20 kHz with a maximum power output of 500 W, was used for synthesis of final title compounds.Infrared (IR) spectra were recorded on JASCO FTIR (PS 4000) using KBr pallet.Melting points were determined in open capillary tubes and are uncorrected.The 1 H-NMR and 13 C-NMR spectra of synthesized compounds were recorded on Bruker Advance II 400 NMR Spectrometer (Billerica, MA, USA) at 400 MHz frequency in deuterated DMSO.Tetra methylsilane (TMS) was used as an internal standard.The chemical shifts are reported as NMR spectra δppmunits.The following abbreviations are used; singlet (s), doublet (d), multiplet (m).Mass spectra were taken with WATERS, Q-TOF MICROMASS (E SI-MS).Elemental analyses were done with a FLASHEA 112 Shimadzu' analyzer (Mumbai, Maharashtra, India) and all analyses were consistent (within 0.4%) with theoretical values.

(B) Ultrasonication Method
Equimolar quantities of indole-2,3-dione (isatin) (1 mmol) (1)and hydrazine hydrate (1mmol) (2) in the presence of catalytic amount of glacial acetic acid in absolute ethanol (5 mL)was sonicated by keeping the reaction mixture in an acoustic box containing Ultrasonic solid probe at 25-40 °C and at 25 amplitude for 15 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 was formed as the product with molecular formula C8H7O1N3; MW: 161.13; yield: 95%; melting point: 282-284 °C.The melting point was uncorrected.
An equimolar quantity of 3-hydrazonoindolin-2-one (1mmol) (3), substituted aromatic aldehyde/heteryl aldehyde (1mmol) (4) and tri-ethylphosphite (5) (1mmol) was stirred at room temperature in absolute ethanol, in the presence of Cerric Ammonium Nitrate (CAN) as a catalyst.The progress of the reaction was monitored by TLC.After completion of the reaction, the reaction mixture was cooled and poured in water, filtered and the solid obtained was dried and recrystallized with ethanol.The time required for completion of reaction varied from 70 to 90 min as shown in Table 1.
A Conventional method for of 9(a-j) derivatives

Conclusions
In conclusion, we have synthesized a suite of novel diethyl (2-(1-(morpholinomethyl)-2-oxoind olin-3-ylidene) hydrazinyl) (substituted phenyl/heteryl) methylphosphonate derivatives 9(a-j) using a green protocol.The structures of the ultrasound synthesized compounds were confirmed by spectral analyses like IR, 1 H NMR, 13 C NMR, 31 P NMR and MS.The mild reaction conditions, excellent yields in shorter reaction times and evasion of cumbersome work procedures make this process economically lucrative for industrial application.

Figure 1 .
Figure 1.The designed protocol for the synthesis of the target compound.

Scheme 1 .
Scheme 1. Scheme of synthesis of the target compounds.

Table 1 .
The physical characterization data of the synthesized derivatives 6

Table 2 .
Physical characterization data of the synthesized derivatives 9

Table 3 .
Synthesis of 9(a-j) derivatives using conventional and ultrasound methods.