Preparation and reactions of 3-[3-(aryl)-1,2,4-oxadiazol-5-yl&#093: propionic acids

Abstract

R.M. Sri vas ta va*, and G.M. Se a bra De par ta men to de Qu í mi ca Fun da men tal, Uni ver si da de Fe de ral de Per nam bu co, Ci da de Uni ver si tá ria, 50.670-901 Re ci fe -PE, Bra zilRe ce i ved: Octo ber 28, 1996 Nes te ar ti go des cre ve mos as sín te ses dos áci dos 3-[3-(aril)-1,2,4-oxadiazol-5-il] pro piô nicos 3a-g , com alto ren di men to, a par tir das ari la mi do xi mas 1a-g e do ani dri do suc cí ni co. Os 1,2,4-oxadiazóis 3a-f tam bém fo ram ob ti dos fa zen do-se a re a ção em um for no de mi cro on das do més ti co. Ava li a ções far ma co ló gi cas pre li mi na res de mons tra ram que os com pos tos 3b-e pos su em pro pri e da des anal gé si cas. Cál cu los ab-initio com base sto-3g fo ram re a li za dos com os com pos tos 3a , 4a , 5a e 6a.The synthe sis of ti tle com pounds 3a-g , from ary la mi do xi mes 1a-g and suc ci nic anhydri de in high yi elds is des cri bed. 1,2,4-Oxadiazoles 3a-f were also ob ta i ned by carr ying out the re acti on in a do mes tic mi cro wa ve oven. Pre li mi nary phar ma co lo gi cal eva lu a ti ons de mon s tra ted that 3b-e pos sess anal ge sic pro per ti es. Ab ini tio mo le cu lar or bi tal cal cu la ti ons of the type STO-3G have been per for med for com pounds 3a , 4a , 5a and 6a . Key words: ary la mi do xi mes, bis-1,2,4-oxadiazoles, di aryl-1,2,4-oxadiazoles, ab-initio sto-3g cal cu la ti ons Intro duc ti onAlthough the synthe sis of acids 3a-g have been des cribed, the ir yi elds were rat her low [2][3][4] . In an at tempt to im prove the yi elds of the se acids, we dis co ve red that he a ting a mix tu re of ary la mi do xi mes 1a-f and suc ci nic anhydri de 2 in a do mes tic mi cro wa ve oven for 10 min pro vi des 3a-f in high yi eld (Sche me 1). The se acids are im por tant be ca u se 3-[3-(phenyl)-1,2,4-oxadiazol-5-yl] pro pi o nic acid ( 3a ) has been found to pos sess sig ni fi cant pe rip he ral anal ge sic and an ti-inflammatory pro per ti es 5 . Com pounds 3b-e , in a pre li mi nary scre e ning, sho wed some anal ge sic pro perty; in fact, 3b and 3d have slightly bet ter ac ti vity than dipy ro ne. Acid 3b also sho wed an ti-inflammatory pro perty but 30 per cent less than in do met ha ci ne 6 .Du ring the pre pa ra ti on of 3a-g , we ca re fully in ves ti gated two mi nor pro ducts and iden ti fi ed them as 4a-f and 5a-f res pec ti vely. We synthe si sed 4a-f from 3a-f in or der to verify the ir iden ti ti es. The li te ra tu re re ports the synthe sis of only 4a , from ben za mi do xi me and suc ci nic anhydri de 7 , and its spec tros co pic pro per ti es 8,9 . Be si des this, no more in for ma ti on was ava i la ble on this class of com pounds.Next we trans for med acids, 3a-g to the ir methyl es ters, 6a-g . None of the methyl es ters were known. The re fo re, this pa per des cri bes the im pro ved synthe sis of 3a-f and the pre pa ra ti ons of 4a-f from 3a-f , and of 6a-g from 3a-g , respec ti vely. Re sults and Dis cus si onThe re ac ti on of ary la mi do xi mes 1a-f with suc ci nic anhydri de 2 was re por ted to yi eld 3a-f in po...

Improved Microwave-Mediated Synthesis of 3-(3-Aryl-1,2,4-oxadiazol-5-yl)propionic Acids and Their Larvicidal and Fungal Growth Inhibitory Properties

“…We observed a relationship between LC 50 values and substituent electronegativity properties: LC 50 F 3eϾLC 50 Cl 3fϾLC 50 Br 3g. Halogenated compounds 3g (LC 50 ϭ15.2 ppm) and 3f (LC 50 ϭ28.1 ppm) may be considered highly active (LC 50 values Ͻ50 ppm) and these LC 50 values are similar to the activity of essential oils obtained from the leaf, stem and inflorescence of Piper marginatum (LC 50 ϭ19.9-23.8 ppm) 42) as well as the leaf of Cryptomeria japonica D. DON (LC 50 ϭ37.6 ppm). 45) Moreover the best LC 50 values for 1,2,4-oxadiazole are comparable to the larvicidal effect of b-asarone, natural botanical insecticide, which have exhibited an LC 100 of 16 ppm.…”

“…As reported in the literature, the above-cited acids were obtained in good yields in 10 min. 42) Since these compounds are gaining more and more significance, we decided to improve their microwave-accelerated synthesis under solventless conditions. With this aim, we performed a few experiments using a specific focused microwave oven.…”

“…In order to get the best yield of these acids, we have chromatographed the crude mixture over silica gel. This way the yield was excellent, 41,42) but this procedure is expensive and time-consuming. In this work we isolated compounds 4a-i and 5a-i, respectively.…”

“…41) Later, these reagents were heated in a household microwave oven under solvent-free conditions for 10 min 42) with better yields in comparison with the solution method. It is now well established that focused microwave reactors are quite superior to the domestic ones due to their ability of focusing energy on the sample producing a faster heating of the reagents.…”

“…41,42) The crude product was dissolved in ethyl acetate (30 ml), then a concentrated aqueous solution of NaHCO 3 (35 ml) was added to it, and the mixture was stirred overnight. The aqueous layer was separated followed by the addition of concentrated aqueous citric acid solution until total precipitation of the desired compound 3a-i occurred.…”