Preparation of trichloroacetoamidoxime in aqueous media and application in one pot synthesis of 1,2,4-oxadiazoles

Oxadiazoles are heterocyclic compounds with a variety application in many pharmaceuticals and agrochemicals products. We reported here the convenient synthesis of 3-trichloromethyl-1,2,4-oxadiazoles from trichoroacetoamidoxime and RC(O)Cl (R= methyl ethyl, propyl, Ph, CH 2 Cl, CHCl 2 , CCl 3 ) by one pot reaction


Introduction
Azoles and derivatives have a long history in medicinal chemistry.2][3] Biologically relevant compounds containing the 1,2,4-oxadiazole moiety also include HIV integrase inhibitors, 4 antituberculostatic agents 5 and antikinetoplastid agents. 62][13][14][15] The major synthetic rote to obtain oxadiazoles is the reaction of amidoximes and acyl chloride promoted by either heat or by bases, such NaH, NaOEt or pyridine.Usually this synthesis involve a two step procedure, the first one is the formation of O-acyl derivative and the second one and intramolecular cyclization with hard conditions (thionyl chloride, phosphorus oxychloride or acid sulfuric).
The common protocol for the preparation of precursor amidoximes includes reactions of hydroxylamines with nitriles, or thioamides. 169] In according with our program research in organic chemistry, in this work, we chose explore the versatility of the trichloroacetoamidoxime 1 as halogen-precursor in a one-pot conversion with acyl chlorides 2a-g to the corresponding 3trichloromethyl-1,2,4-oxadiazoles 3a-g with good yields.

Results and Discussion
][22][23] The precursor trichloroacetoamidoxime 1 could be easily synthesized by reaction of trichloroacetonitrile and hydroxylamine hydrochloride in water at room temperature for 3 hours in 90% yield (Scheme 1).This yield was better than the literature (64%).In preliminary experiments, we have observed that the reaction between amidoxime 1 with trichloroacetyl chloride 2e was solvent and temperature dependent.When the reaction was carried out at low boiling point solvent such as ethyl ether, chloroform or dichloromethane, the starting materials were recovered and we did not observe the formation of the product (entry 1, 2 and 3 -Table 1).In our studies, we found that the toluene was the appropriated solvent for these reactions giving the best results.The increased of temperature raise the formation of 1,2,4oxadiazoles in excellent yield (entry 5 and 6, Table 1).The reaction was monitored by TLC (thin layer chromatography).The important particularity of this reaction process is the work-up, in which we observed that the use of successive treatment with solution of Na 2 CO 3 gave the products without purifications.The 5-substituted-3-trichloromethyl-1,2,4-oxadiazoles 3a-g were synthesized by treatment of trichloroacetiamidoxime 1 with acyl chlorides 2a-g using toluene for 20 hours at 100°C (Scheme 2).The compounds 3a-g were obtained in good yields (60-90%).The scope and generality of this process is illustrated by a series of seven oxadiazoles and the results are presented in Table 2.The products were identified concerning both analytical and spectral data ( 1 H NMR and 13 C NMR) of all compounds are in full agreement with the proposed structure.

Conclusions
In conclusion, we have described the facile preparation of trichloroacetoamidoxime 1 in aqueous media, and its application in an one-pot approach to the synthesis of 1,2,4-oxadiazoles in good yields.This method works well with a variety of acyl chlorides.

Experimental Section
General.Starting trichloroacetoamidoxime 1 was prepared from of our procedure.All solvents and reagents were obtained from Aldrich and used without further purification.The data of NMR spectra were recorded on a Bruker DPX 400 ( 1 H at 400.13 MHz and for 13 C at 100.63 MHz) spectrometer, 5 mm sample tubs, 298 K, digital resolution of ± 0.01 ppm, 0,5 M in CDCl 3 , containing TMS as internal standard.Mass spectra were registered in HP 6890 GC connected to HP 5973 MSD and interfaced by a Pentium PC.The CG was equipped with a split-splitless injector, autosampler, cross-linked HP-5 capillary column (30m, 0,32 mm of internal diameter), and helium was used as the carrier gas.

General procedures. Trichloroacetoamidoxime (1)
A mixture of hydroxylamine hydrochloride 2.36g (3.5 mmol) and NaOH 1.36g (3.5mmol) in water was added trichloroacetonitrile 1.7 mL (1.7 mmol).The mixture was stirred at room temperature for 3 h.For the compound 1 a solid was observed.The product was isolated by filtered, dried in a vacuum and recrystalized in gradient hexane/acetate (3:1).