An efficient synthesis of phosphonate derivatives and stable phosphorus ylids by three-component reaction between phosphines or phosphites, benzil hydrazone and dialkyl acetylenedicarboxylates

Three-component reaction between trialkyl phosphites, dialkyl acetylenedicarboxylates and benzil hydrazone afforded phosphonate derivatives. Similar reaction between triphenylphosphine, dialkyl acetylenedicarboxylates and benzil hydrazone led to stable phosphorus ylides. When tri(n-octyl)phosphine was treated with dialkyl acetylenedicarboxylates and benzil hydrazone cyclic phosphorus ylide derivatives were obtained as the only product. All reactions were conducted in CH 2 Cl 2 as solvent at room temperature without using any catalyst and the stable products were obtained in high yields


Introduction
The importance of organophosphorus compounds as main materials in organic synthesis and synthesis of a number of natural products has been very actively studied and proven in organic laboratories in recent years.Among these, phosphorus ylides are of special importance.They are serious reactive intermediates in synthesis of heterocyclic compounds.Phosphorus ylides, have a special electronic and molecular structure, they are sorted as special zwitterions.Also they are described by electron-rich carbanions, decisively nucleophilic.2][3][4][5][6] Phosphorus ylides are generally synthesized from deprotonation of phosphonium salts which, in turn are created by the reaction of alkyl halides with phosphine nucleophiles. 7Phosphonates are other organic compounds that contain phosphorus.Phosphonates have increasingly used as reagents in synthetic organic chemistry and as biologically and industrially important compounds. 8Phosphonate derivatives also attracted much attention as pesticides, insecticides, antibiotics, blood pressure regulators, antiviral agents, anti-HIV agents, and herbicides. 9Phosphonate moieties are also found applications as therapeutic drugs. 10,11They are also increasingly used in medicine to treat disorders associated with bone formation and calcium metabolism. 12,13eaction between trivalent phosphorus nucleophiles and dialkyl acetylenedicarboxylates (DAADs) in the presence of organic compounds with acidic CH, NH, SH or OH groups has been extensively used for synthesis of phosphorus compounds.When triphenylphosphine is used as the phosphorus nucleophile, the product is usually phosphorane derivatives which may be converted to carbocyclic or heterocyclic organic compounds by intramolecular Wittig reaction. 15][16][17] Here we wish to report the results of our study on the reaction of triphenyl or tri(n-octyl)phosphine and trialkyl phosphites with DAADs in the presence of benzil hydrazone.

Results and Discussion
At first, the reaction between trialkyl phosphites, DAADs and benzil hydrazone was studied (Scheme 1).Dimethyl acetylenedicarboxylate (DMAD, 2a) was added to a mixture of triethyl phosphite (3a) and benzil hydrazone (1) in CH2Cl2 as solvent at room temperature.After 12 hours the TLC analysis of the reaction mixture showed the presence of only one product which was isolated and its structure was proved by IR and NMR spectral and elemental analysis data as phosphonate 4a.The 1 H NMR spectrum of 4a showed multiplet signals at 1.16-1.28ppm for two CH3 of ethoxycarbonyl groups and two singlet signals at 3.66 and 3.75 ppm for two methoxy groups.Two aliphatic CH protons were observed as a dd ( 3 JHH 5 Hz, 2 JPH 25 Hz) signal at 3.81 ppm and a dt ( 3 JHH 5Hz, 3 JHH 5Hz, 3 JPH 9Hz) signal at 4.80 ppm.The aromatic and NH protons were observed as multiplet signals at 7.35-8.05ppm. 1 H decoupled 13 C NMR spectrum of 4a showed 20 distinct resonances in agreement with the suggested structure.Structure of 4a was also confirmed by the IR spectrum showing absorption bands at 3249 and 1726 cm -1 for NH and ester carbonyl groups, respectively.
Compounds 4a-c possess two stereogenic centers in their structure and may exist as two diastereomers.The NMR spectra of these compounds showed that the reaction is diastereoselective and only one diastereomer was observed for these compounds.© AUTHOR(S) Three-component reaction between triphenylphosphine, DAADs and benzil hydrazone was also studied (Scheme 2).The reaction between triphenylphosphine, DMAD and benzil hydrazone afforded phosphorane derivative 6a in 95% yield.Compound 6a was easily isolated and purified by simple washing of the solid product with diethyl ether and its structure was proved by IR and NMR spectral and elemental analysis data.The NMR spectra of phosphoranes 6a exhibited a mixture of two rotational isomers.The ylide moiety of these compounds is strongly conjugated with the adjacent carbonyl group and the rotation about the partial double bond in 6-(E) and 6-(Z) geometrical isomer pairs is slow on the NMR timescale at ambient temperature (Scheme 3).The 1 H NMR spectrum of 6a showed four sharp lines (3.37, 3.67, 3.10 and 3.71 ppm) for methoxy protons along with signals for methine proton at 4.16 and 4,18 ppm, which appear as two triplets for the major and minor geometrical isomers.Similar reaction between PPh3, DEAD and benzil hydrazone afforded phosphorane 6b in 90% yield.
When tri(n-octyl)phosphine was used as the phosphorus nucleophile in reaction with DAADs and benzil hydrazone β-lactam derivatives 8a and 8b were obtained in good yields (Scheme 4).The 1 H NMR spectrum of 8a showed a triplet signal at 0.87 ppm for three CH3 of n-octyl.The other protons of n-octyl groups resonated at 1.14-1.50ppm and 2.30 ppm as multiplet signals.The methoxy protons resonated as a single signal at 3.80 ppm.The aliphatic CH group was observed at 7.01 ppm as a single signal.The aromatic protons were observed at 7.35-7.50ppm.Structure 8a was also confirmed by the IR spectrum showing absorption band at 1726 and 1604 cm -1 for ester and amid carbonyl groups, respectively.Conjugation with negative charge accounts for the reduction of the wavenumber of the carbonyl absorption band of amid group.The IR spectra of compounds 8a and 8b didn't show the absorption band for the NH group.The 1 H and 13 C NMR spectral data also confirmed the removal of one of the alkoxy groups of DMAD or DEAD for formation of compounds 8a or 8b.On the basis of the well-established chemistry of trivalent phosphorus nucleophiles 1,3-5 a reliable mechanism for formation of phosphonates 4a-c and phosphoranes 6a-b and 8a-b is suggested in Scheme 5.It is reasonable to assume that compounds 4, 6 and 8 resulted from the initial addition of phosphorus nucleophile to DAAD as a Michael acceptor to generate the inert salt intermediate 9 which was protonated by benzil hydrazone.At the next step, the positively charged ion 11 was attacked by the conjugate base of benzil hydrazone (10) to afford phosphorus ylide 12.In cases that trialkyl phosphites were used, the phosphite ylide 12 hydrolyzed to phosphonate derivatives 4a-c.In cases when tri(n-octyl)phosphine was used the phosphorane 12 converted to products 8a-b by a cyclization reaction with removal of an alcohol molecule.© AUTHOR(S)

Conclusions
We report herein a simple route for synthesis of some new phosphonate derivatives by three-component reaction between triethyl or trimethyl phosphite, benzil hydrazone and dialkyl acetylenedicarboxylate.Similar reaction between triphenylphosphine or tri(n-octyl)phosphine, benzil hydrazone and dialkyl acetylenedicarboxylate leads to phosphorane derivatives in good yields.The advantages of the method are readily available starting materials, simple and neutral reaction conditions, and high yields of products.

Experimental Section
General.All solvents and chemicals were purchased from commercial sources and used without further purification.The utilized benzil hydrazone was prepared by reaction of benzil with hydrazine hydrate on the basis of the reported procedure. 18IR spectra were recorded on a Shimadzu IR-470 spectrometer.NMR spectra were recorded on a Varian model UNITY Inova 500 MHz (1H: 500 13C: 125 MHz) NMR spectrometer.Chemical shifts of 1 H, 13 C and 31 P NMR are reported in parts per million (ppm) from tetramethylsilane (TMS) as an internal standard in CDCl3 as solvent.
General procedure for synthesis of phosphonate derivatives 4a-c.Dialkyl acetylenedicarboxylate (1 mmol) was added dropwise to the mixture of trimethyl or triethyl phosphite (1 mmol) and benzil hydrazone (1 mmol) in CH2Cl2 at room temperature.The reaction mixture was then stirred at room temperature for 12 hours.The solvent was removed under reduced pressure, and the residue was purified by silica-gel column chromatography using ethyl acetate-hexane (1:4) mixture as eluent.