A Handy and Solventless Direct Route to Primary 3-[3-aryl)- 1,2,4-oxadiazol-5-yl]propionamides Using Microwave Irradiation

A one-step, simple and straightforward synthesis of the title amides from the corresponding carboxylic acids, urea and imidazole under microwave irradiation is described.


Introduction
1,2,4 Oxadiazoles are well known compounds which exhibit diversified biological activities [1][2][3][4].The work from our laboratory also cites other pharmacological properties previously reported by other researchers [5,6].The analgesic and antiinflammatory effects of 5-methyl-3-phenyl-1,2,4-oxadiazole were discovered as early as in 1972 [7].Incorporation of a carboxyl function into the C-5 side-chain of 1,2,4-oxadiazoles improves both analgesic and antiinflammatory properties [8].Similar pharmacological properties have been displayed by carboxylic acid amides as well [9,10] and incorporation of a carboxylic acid derivative, like an amide, might result in different biological activity.For example, while lysergic acid is inactive, its N,N-diethylamide derivative (LSD) thoroughly changes the human behavior and causes psychic alterations and hallucinations at doses as low as 1mg/kg body weight [11].Although the preparation of amides using conventional procedures is well documented [12,13], clean, fast and less cumbersome methods are less common.A literature search did reveal some reports of the preparation of amides using microwave radiation [14a-d-18], but mostly dealing with secondary and tertiary amides.Two reports describe preparation of primary amides, one employing carboxylic acid, imidazole and urea [19] and the other using carboxylic acid, urea and pyridine [20].On the other hand 1,2,4-oxadiazoles containing a primary amide function in their C-5 side-chain have drawn practically no attention.Two companies market 3-[3-phenyl-1,2,4-oxadiazol-5yl]propionamide (4a, [21a,b], but no experimental details are available.Because of the great significance of the amide functionality, we wished to develop a speedy, eco-friendly and solvent-free technique to obtain such compounds.Herein, we report the synthesis of six 3-[3-(aryl)-1,2,4oxadiazol-5-yl]propionamides 4a-f under solvent-free conditions employing an unmodified domestic microwave oven [22] (Scheme 1).The reactions are clean, the work-up is simple and the yields are relatively high (Table 1).Scheme 1. Preparation of 4a-f from 1a-f and 2. ,

Results and Discussion
Based upon previous suggestions concerning the reaction of a carboxylic acid and imidazole [14,23], Khalafi-Nezhad et al. [19] proposed the formation of an imidazolium carboxylate salt, which absorbs microwave energy.The energy increase then causes the decomposition of urea followed by proton exchange with the imidazolium ion and subsequent formation of a ammonium carboxylate salt which furnishes an amide.Aside from this, the mechanism of primary amide formation from an acid, imidazole and urea has not been discussed.To us, the decomposition of the ammonium carboxylate salt at a relatively low temperature and in such a short time seems difficult.In order to know whether an ammonium salt of a carboxylic acid is responsible for the amide formation, we took readily available ammonium benzoate and subjected it to microwave irradiation under conditions similar to those described earlier.Ammonium benzoate remained unchanged as verified by TLC and the melting point of the crystals.This indicates that ammonium salts is not responsible for primary amide formation in such a reaction.Therefore, we postulate a different mechanism, in which the highly reactive iminoketene 9, formed through reaction of urea with imidazolium ion, is the main agent in the transformation of the carboxylate into an amide: nucleophilic attack of the carboxylate on the iminoketene, followed by proton exchange with imidazolium ion results in 11 which, through a S N i reaction similar to the formation of acyl halides with SOCl 2 , gives the amide.This mechanism is more logical and is being proposed here for the first time (Scheme 2).Scheme 2. Mechanism of formation of primary amides 4a-f from 3a-f in the presence of imidazole and urea under microwave irradiation.

General
Melting points were determined on an Electrothermal (Mel-Temp) apparatus (Model No. 1002D) and are uncorrected.All reactions were monitored by TLC analysis (TLC plates GF 254 Merck).IR spectra were measured with a IFS66 Bruker spectrometer employing KBr disks. 1 H-NMR spectra were recorded with a Varian Unity Plus 300 MHz spectrometer using SiMe 4 as an internal standard.All reactions were conduced in a Sanyo domestic microwave oven model EM-300B (220v/650W/2450 MHz).

General Synthetic Procedure
An appropriate arylamidoxime 1a-f (1.0 mmol) was allowed to react with succinic anhydride (2, 1.1 mmol) in a domestic microwave oven following the procedure reported earlier to afford 3a-f [22].A mixture of an appropiate acid 3a-f (1.0 mmol), imidazole (1.5 mmol) and urea (3.0 mmol) were well triturated and placed in a small glass test tube followed by irradiation for 6.0 min.in an unmodified domestic microwave oven (50% power) and then cooled.The solid was treated with ethyl acetate and filtered to remove the insoluble material.TLC analysis (elution with 5.0:4.5:0.5 benzene-ethyl acetatemethanol, followed by visualization under ultraviolet light) showed spots with R f values ranging from 0.19-0.28.The product dissolved in ethyl acetate was applied to a thick-layer chromatographic plate and developed with the above-mentioned solvent mixture.Work-up furnished chromatographically pure primary amides 4a-f.The main experimental details for each case are compiled in Table 1.

Table 1 .
Observed experimental results for the synthesis of 4a-f.Compound ReactionTemp.(°C)a Yield (%) b R f values c M.p (° C) a Temperature recorded by a Minipa model 350 infrared thermometer.b Chromatographically pure material.c Solvent system: 5.0:4.5:0.5 benzene-ethyl acetate-methanol.d Crystallized from chloroform containing a little ethyl acetate.