Indian Journal of Chemistry Vol. 55B, July 2016, pp. 833-853 Advances in Contemporary Research Advanced synthetic and pharmacological aspects of 1,3-oxazoles and benzoxazoles Ambreen Ghani*, Erum A Hussain, Zubi Sadiq & Narjis Naz Department of Chemistry, Lahore College for Women University, Lahore 54000, Pakistan E-mail: [email protected]; [email protected] Received 9 December 2014; accepted (revised) 31 March 2016 Broad bio-spectrum of 1,3-oxazole and benzoxazole has created an attractive platform for synthetic chemists to introduce structural modification in its nucleus by straight forward access to new approaches. Owing to its fascinating features and interesting pharmacological activities, many researchers have proved that oxazole is an active agent in treating different diseases. Based on this fact, this article outlines intramolecular and two component intermolecular cyclization to oxazoles and benzoxazoles. The theme is well documented in this review article covering the era from 2007 till present. Moreover, bioactivity and mechanistic insights are provided with different synthetic approaches, encompassing various pathways. Keywords: Benzoxazole, bisoxazole, oxazole, synthesis, bioactivity Oxazole, a heterocyclic scaffold is believed to occur overcome the limitations of multi-step processes11-14. in various structurally complex biologically active The amazing pharmacological profile of oxazole natural products. Several oxazole possessing includes antibiotic, anti-inflammatory, hyperglycemic, compounds have been isolated from plants and marine antiproliferative, antihistaminic, antiparasitics and natural origins such as Martefragin A and Almazol D anti-tuberculosis activities15-17. For instance, the use of (Figure 1) isolated from Martensia fragiles1 and red drug containing oxazole is oxaprozin having non- algae2 respectively. These naturally occurring steroidal anti-inflammatory activity. Owing to its molecules demonstrate the versatile synthetic, privileged importance, a lot of work has been done on medicinal and industrial applications of oxazoles. The synthesis and medicinal features of oxazoles18. diversified oxazole analogues with multi-directional To the best of our knowledge, previous reviews19 potential stands out in modern organic chemistry and on oxazole focused on specific aspects of its synthesis provides the sharp sword that combat future were published during 2008 to 2014. We hereby wish challenges related to medicinal and synthetic aspects. to describe synthetic routes involving metal catalyzed, Considerable attention has been made in metal free, microwave assisted and different formulating high yield synthetic approaches from multicomponent domino approaches adopted for simpler chemical catalog. Generally, this widespread oxazoles. Metal catalyzed procedures have been highly substituted building block is attained from studied by emphasizing their specificity, while their intramolecular cyclocondensation reactions using promising mechanistic insight has also been provided. dehydrating agents or by intermolecular cyclization Metal free transformations for oxazoles, contribute a through α-substituted ketones as intermediates3-10. great deal in organic synthesis. Microwave Nevertheless, direct eco-friendly metal catalyzed technology being highly preferred method of heating approaches have also been extensively used that provides better possibilities in chemical synthesis. While MCR approach offer a clear direction with NH atom economy, ecofriendly simplified steps and RO N effective use of resources for 1,3-oxazoles. OOC O N O In the preceding sections a brief description of O N numerous synthetic strategies and pharmacological implications of 1,3-oxazole hetrocycles is presented in N N H H order to provide an idea for future directions on this Figure 1 — Oxazoles from natural sources potential molecule. 834 INDIAN J. CHEM., SEC B, JULY 2016 Intramolecular Cyclization X ° O O [Cu], H2O, 120 R' Amide based oxazoles ' N R N R R Benzo[d]oxazole 2 was successfully synthesized from H R2N NR2 1 2 intramolecular O-arylation of haloanilides 1 using feasible 20 protocols . This direct approach was environmentally Scheme I benign and highly cost effective due to open choice in copper salt and simple diamine derivatives, Scheme I. A direct approach to 2-substituted 5-oxazole The copper catalyzed oxidative cyclization of carbaldehydes was achieved by palladium (II) salt enamides furnished 2,5-disubstituted oxazoles in two catalyzed intramolecular heterocyclization of alkyl, 21 steps from alkyne and simple amide precursors . An aryl and heteroaryl propargylamides27. interesting synthesis of 2-phenyl-4,5-substituted N-Propargylamides also produced 2,5-disubstituted oxazoles in a couple of steps involving copper mediated oxazoles with aryl iodides by same catalyst through intramolecular cyclization of substituted β-(methylthio) in situ cyclization of coupling product28. enamides was reported. Two steps copper promoted Various rhodium catalysts for cyclodehydration cyclization of β-(methylthio)enamides generated and carbene N-H insertion were used successfully to from 4-[(methylthio)hetro(aryl)methylene]-2-phenyl- achieve regioselective sulfones, phosphonates and 5-oxazolones afforded functionalized 2-phenyl-4,5- carboxylates of oxazoles and thiazoles29. The substituted oxazoles. Texamine and uguenenazole, α-silylalkyl benzoxazoles 6a and oxazoles 6b were two natural, 2, 5-diaryloxazoles were furnished prepared from silyldiazoketones 3 via silylketenes 4 through hydrolysis and decarboxylation of 2,5- which subsequently combined with amino malonate diaryloxazole-4-carboxylates. Furthermore, oxazole- and amino phenols followed by cyclocondensation to 4-carboxamides derived from serine to trisubstituted give desired products (Scheme II)30. 4,2-bisoxazoles was elaborated via diethylaminosulfur Greatly regioselective migration of the sulfonyl trifluoride/1,8-diazabicyclo[5.4.0] undec-7-ene group lead to functionalized oxazoles 8a and 8b by (DAST/DBU) facilitated through cyclodehydration- virtue of silver (I) promoted [3,3] rearrangement of 22 dehydrohalogenation arrangement . N-sulfonyl propargylamide 7 (Scheme III)31. Nucleophilic ring opening of 4-[(methylthio) Silver promoted cyclization of amides and hetro(aryl)methylene]-2-phenyl-5-oxazolone was obtained α-bromoketones in microwave was determined by by alkyl/aryl grignard reagents, amino acid esters, Bailey. The scope of the reaction was extended to amines and alkoxides, so different functionalities like both the variety of silver catalyst and amide substrates ester, acyl, N-substituted carboxamide were to produce highly functionalized 2,4 and 2,4,5 introduced at C-4 of oxazole. Regioselective substituted oxazoles32. functionalized molecules of 2-arylbenzoxazoles were Atom-economic approach was adopted to have a prepared by copper-mediated intramolecular oxidative group of functionalized 2,5-disubstituted oxazoles 10 23 coupling of benzanilides . from propargylic amides 9 catalyzed by gold to Fabrication of alkyl, aryl, hetero aryl and vinyl alkylidene oxazolines, followed by autoxidation to substituted oxazoles by copper catalyzed oxidative hydroperoxides (Scheme IV)33. cyclization of enamides through functionalization of Various important oxazoles from enamides by 24 vinylic C-H bond was obtained by Cheung . phenyliodinediacetate mediated intramolecular More recently, Panda revealed a proficient one pot cyclization were achieved. The extensive substrate annulation of enamides to 2,5 and 2,4,5-substituted choice and metal free oxidative carbon-oxygen bond 34 oxazoles through NBS/Me2S catalysed reaction in formation was the main characteristics of this method . mild base. The scope of this method has been A transition metal free protocol to present thoroughly explored including both electron donating quinoline, pyridine and coumarin annulated oxazoles 25 and withdrawing groups . An efficient, simple and (Figure 2) using Cs2CO3 through intramolecular ligand-free preparation of substituted benzoxazoles, nucleophilic cyclization of o-bromoamides to benzimidazoles, 2-aminobenzothiazoles and 2-amino fabricate C-O bond for oxazoles was exposed35. benzimidazoles were carried out from o-bromoaryl A catalyst free domino strategy was adopted to derivatives via intramoleculer cyclization through assemble 2-acyloxazoles from arylacetylenes, methyl 26 recoverable copper (II) oxide nanoparticles . ketones, or arylethenes via successive iodination/ GHANI et al.: 1,3-OXAZOLES AND BENZOXAZOLES 835 O O Rh (oct) O O SiR 2 4 C -NH2-C6H6OH R R 3 N R SiR H N2 3 SiR3 OH 4 3 5a CO2Et NEt NEt3 PPh3, DEAD 3 EtO2C NH3Cl O CO Et R O OEt 2 R O R PPh3, I2 N CO Et N 2 R Si N R3Si CO2Et H 3 NEt3 SiR3 6a 6b 5b Scheme II O COOH O Au1 AgBF R O O 4 2 O RN R2 O R 2 H O2 R N R1 N O 9 10 O Ts 8a Scheme IV R1 N R2 CO2CH3 CO2CH3 Ts O DBU, ACN 7 Et3N N R2 HN AgBF R N Br/I O 4 1 R O R 8b 11 12 Scheme III Scheme V O O Cl O Me EtN O O O N N N N Br Figure 2 — Cesium catalyzed oxazoles Kornblum oxidation/cyclization36. 2,5-Disubstituted Robinson-Gabriel synthesis utilizing β-oxotryptophan oxazole-4-carboxylate 12 was synthesized from and β-oxotryptamine methyl ester with chiral methyl esters of N-acyl-β-halodehydroamino butyric ketoamides leading to target molecule. This revision acid 11 in 2% DBU-acetonitrile, for investigating was justified on the basis of NMR and optical activity photophysical properties (Scheme V). All the of synthetic and natural Almazole D2. derivatives showed moderate solvent