Efficient synthesis of furo[2,3-d ]pyrimidin-4(3 H )-ones

The carbodiimides 4 , obtained from reactions of iminophosphorane 3 with aromatic isocyanates, reacted with amines or phenols to give 2-substituted furo[2,3-d]pyrimidin-4(3 H )-ones 6 in the presence of catalytic amount of sodium alkoxide or solid potassium carbonate in good yields.


Introduction
The derivatives of fused pyrimidinones are valued not only for their rich and varied chemistry, but also for many important biological properties.][7][8][9][10] This is probably due to the instability of the furan ring especially under harsh reaction conditions.Therefore, the development of an efficient method for the preparation of furo [2,3-d]pyrimidinone derivatives under mild conditions is desirable.A key requirement for the facile synthesis of furo [2,3d]pyrimidinones is the use of an effective electron-withdrawing group in order to protect the electron-rich furans from polymerization reactions.The ester group is a very useful electronwithdrawing protecting group since carboxylic ester furans are relatively easy to prepare and are extremely stable.Such protection allows for further functionalization of the furan ring.

Results and Discussion
Diethyl 2-amino-5-methylfuran-3,4-dicarboxylate 2 was prepared from reaction of ethyl 2chloroacetoacetate 1 with ethyl cyanoacetate in the presence of sodium ethoxide in only 58% yield according to literature report 22 .However, we found that when triethylamine was used as a base in place of sodium ethoxide, compound 2 was obtained in 88% yield.The good yield may be due to the mild conditions as weak base triethylamine was used.Compound 2 was further converted to iminophosphorane 3 via reaction with triphenylphosphine, hexachloroethane and triethylamine in good yield (Scheme 1).Iminophosphorane 3 reacted with aromatic isocyanates at 0-5 °C to give carbodiimides 4, which were allowed to react with secondary amines to provide guanidine intermediates 5.In the presence of catalytic amount of sodium ethoxide, the intermediates 5 were converted easily to 2dialkylamino furo [2,3-d]pyrimidin-4(3H)-ones 6a-h in satisfactory yields at room temperature (Scheme 2).The reaction of carbodiimide 4 with phenols in the presence of a catalytic amount of anhydrous potassium carbonate produces 2-aryloxyfuro [2,3-d]pyrimidin-4(3H)-ones 6i-o in good yields at 50-60°C.No matter whether the substituents on the phenols are electron-withdrawing or electron-releasing groups, the cyclization can be completed smoothly under mild conditions.The results are listed in Table 1.The structures of compound 6 were established based on their NMR, MS, IR and elementary analysis.For example the 1 H NMR spectral data of 6a show the signals of -OCH 2 or -NCH 2 at 4.36 or 3.13 ppm as quartets, signals of CH 3 at 2.62, 1.37 or 0.86 ppm as singlet or triplets.The phenyl signals appeared at 7.46-7.28ppm.In the IR spectrum of compound 6a, the strong stretching vibration peak of two C=O appears at 1707 cm -1 .The MS spectrum of 6a shows molecule ion peak (M + ) at m/z 369 with 100% abundance.
In conclusion, we have developed an efficient synthesis of various substituted furo[2,3d]pyrimidin-4(3H)-ones in good yield via aza-Wittig reaction of an iminophosphorane.Due to the easily accessible and versatile starting material, this method has the potential in synthesis of many biologically and pharmaceutically active furopyrimidinone derivatives.

Experimental Section
General Procedures.Melting points are uncorrected.MS were measured on a Finnigan Trace MS spectrometer.IR spectra were recorded on a PE-983 infrared spectrometer as KBr pellets with absorption in cm -1 .NMR spectra were recorded in CDCl 3 on a Varian Mercury 400 spectrometer and resonances are given in ppm (δ) relative to TMS.Elementary analyses were taken on a Vario EL III elementary analysis instrument.

General preparation of 2-dialkylaminofuro[2,3-d]pyrimidines 6a-6h
To a solution of iminophosphorane 3 (1.0 g, 2 mmol) in dry methylene chloride (15 mL) was added aromatic isocyanate (2 mmol) under nitrogen at room temperature.After the reaction mixture was stood for 8-12 hours at 0-5 °C, the solvent was removed off under reduced pressure and ether/petroleum ether (1:2, 20 mL) was added to precipitate triphenylphosphine oxide.After filtration the solvent was removed to give carbodiimide 4, which was used directly without further purification.To the solution of 4 prepared above in methylene chloride (15 ml) was added dialkylamine (2 mmol).After the reaction mixture was allowed to stand for 0.5-6 h, the solution was condensed and anhyd.EtOH (8 mL) with EtONa (0.3 mmol, 10% equiv) in EtOH was added.The mixture was stirred for 4-6 h at r. t.The solution was condensed and the residue was recrystallized from EtOH to give 6a-6h.