One-pot synthesis of stable phosphorus ylides by three-component reaction between arylglyoxals, phosphines and barbituric or Meldrum’s acid

An efficient one-pot method for the synthesis of new substituted phosphorus ylides is described via three-component reaction between arylglyoxals, C – H acids such as barbituric acid and Meldrum ’s acid and triphenylphosphine or tri-n -octylphosphine. This reaction was carried out in boiling ethanol in the absence of any catalyst to afford the products in good to excellent yields


Introduction
Phosphorus ylides are important reactive intermediates in organic synthesis, and are also main starting materials used in syntheses of a number of natural products.They are important intermediates in synthesis of heterocyclic compounds by the Wittig reaction.2][3][4][5][6] Although many ylides are commercially available, it is often necessary to create them synthetically.Phosphorus ylides are commonly obtained from deprotonation of phosphonium salts which, in turn are produced by the reaction of alkyl halides with phosphine nucleophiles.2][3][4][5][6] Three-component reaction of triphenylphosphine, electron-deficient acetylene diesters and acidic organic compounds has also been previously reported for synthesis of stable 1,2-and 1,4-phosphorus ylides. 7In continuation of our previous works on synthesis of phosphorus and nitrogen ylides, 8,9 here we have developed a simple and efficient method for preparation of stable phosphorus ylides by a three-component reaction between arylglyoxals, phosphines, and C-H acidic organic compounds such as Meldrum's acid or barbituric acid.

Results and Discussion
In order to investigate the three-component reaction of arylglyoxals, C-H acidic organic compounds and phosphines at first we studied the reaction between 4-methylphenylglyoxal monohydrate 1a, barbituric acid 3a and triphenylphosphine 2a in ethanol as solvent (Scheme 1).A mixture of 4-methylphenylglyoxal monohydrate and barbituric acid 3a was stirred in ethanol at room temperature.After thirty minutes triphenylphosphine 2a was added and the mixture was stirred in boiling ethanol for 3 hours.The reaction course was monitored by TLC.After 3 hours the product was filtered off and washed with ethyl acetate to afford 5-(2-oxo-2-(p-tolyl)-1-(triphenylphosphoranylidene)ethyl)pyrimidine-2,4,6(1H,3H,5H)-trione 4a in 90% yield.To explore the scope of this reaction, various arylglyoxals were reacted with triphenylphosphine or trioctylphosphine and barbituric acid and the related ylides 4b-e were obtained in good yields.The reaction was also examined with aryglyoxals, Meldrum's acid and triphenylphosphine or trioctylphosphine and the related phosphorus ylides 4f-i were isolated in high yields.The reaction was also carried out with linear 1,3dicarbonyl compounds such as acetylacetone or methyl acetoacetate, but no product could be isolated from the complex reaction mixture.We also could not isolate any product from the reaction of dimedone with arylglyoxals and triphenylphosphine.
Table 1.Synthesis of stable phosphorus ylides by three-component reaction between arylglyoxal monohydrates, phosphines and C-H acidic organic compounds The structures of products 4a-i were deduced from their elemental analyses and their infrared (IR), 1 H NMR, and 13 C NMR spectral data.The IR spectrum of 4a exhibited absorption bands at 1678 cm −1 for carbonyl groups.The N-H stretching absorption band becomes visible at 3437 cm −1 .The 500-MHz 1 H NMR spectrum of 4a showed a single signal at 2.32 ppm for the methyl group.The proton of CH was observed at 6.94 ppm as a doublet signal ( 3 JPH =7.9 Hz), and the aromatic protons exhibited multiplets at 7.21-7.83ppm.The NH proton resonated at 9.36 ppm as a single signal.The 13 C NMR spectra of 4a showed fourteen distinct signals in agreement with the proposed structure.The ylide carbon was observed at 50.3 ppm as a doublet with 13 C-31 P coupling constant of 58.7 Hz.The 31 P NMR spectrum of compound 4a showed a signal at 23.2 ppm for phosphorus atom.
The suggested mechanism for formation of the phosphorus ylides 4a-i is shown in Scheme 2. The Knoevenagel condensation of arylglyoxal monohydrate 1 and C-H acid 3 afforded the enone intermediate 5.
The Michael addition of triphenylphosphine to 5 lead to zwitterionic intermediate 6 which then converted to product 4a by a proton shift (Scheme 2 ).
Scheme 2. The suggested mechanism for formation of the phosphorus ylides 4a-i.
We also investigated the reaction of trimethyl phosphite, arylglyoxals and barbituric acid.The only isolated product was the O-methylated barbituric acid 8 which was obtained in 95% yield.No product could be isolated from similar treatment with Meldrum's acid.A rational mechanism for formation of compound 8 is presented in Scheme 4. The addition of trimethyl phosphite to arylglyoxal afforded the dioxaphospholane intermediate 9 which can methylate barbituric acid 3a to afford the isolated product 8. Scheme 3. The reaction of trimethyl phosphite, arylglyoxals and barbituric acid.

Conclusions
In conclusion we report here an efficient one-pot method for synthesis of new substituted phosphorus ylide derivatives by a three-component reaction between arylglyoxals, C-H acids such as barbituric acid or Meldrum's acid and phosphines.The advantages of the method are the available simple starting materials, simple and neutral reaction conditions, simple isolation and purification of products and high yields of products.

Experimental Section
General.All solvents and chemicals except arylglyoxals were purchased from commercial sources and used without further purification.The utilized arylglyoxals were prepared by the SeO2-oxidation of the related aryl methylketones on the basis of the reported procedure, and used as their monohydrates. 10Melting points were determined on a Melt-Tem II melting point apparatus and are uncorrected.IR spectra were recorded on a Shimadzu IR-470 spectrometer.All of the NMR spectra were recorded on a Varian model UNITY Inova 500 MHz ( 1 H: 500 13 C: 125 MHz) NMR spectrometer.Chemical shifts of 1 H, 13 C NMR are reported in parts per million (ppm) from tetramethylsilane (TMS) as an internal standard in DMSO-d6 as a solvent.
General procedure.A mixture of arylglyoxal (1 mmol) and C-H acid (1 mmol) in ethanol (15 mL) was stirred at room temperature for 30 min.Then, triphenylphosphine or trioctylphosphine (1 mmol) was added to this mixture.The reaction mixture was then stirred at reflux temperature for 3 h.The solvent was removed under reduced pressure, and the residue was washed by ethyl acetate (2 x 10mL) to afford the pure product.

8 Scheme 4 .
Scheme 4. Suggested mechanism for formation of compound 8 from the reaction of trimethyl phosphite, arylglyoxals and barbituric acid.