Advances in Contemporary Research Advanced Synthetic And

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 intramolecular O-arylation of haloanilides 1 using feasible 1 2 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 EtO2CNH3Cl

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 6b 6a 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 sensitivity and Synthesis and comparative studies of oxazoles and high florescence quantum yield which proved it as benzothiazole derivatives were carried out and 37 good florescent probs . explored the later more effective than oxazoles Hernandez et al.38,15 utilized convergent synthetic against all microorganisms. Oxazoles were prepared strategy via intramolecular Hantzsch macrocyclization via dehydration of hippuric acid 13 to give azalactone for preparation of 2,4-concatenated oxazoles 14, which on alkylation and dehydration resulted in (Figure 3). Two oxazole rings were united 16 (Scheme VI). Antimicrobial benzothiazole simultaneously from oxazole containing peptides derivatives were furnished by a multistep sequence using DAST under mild alkaline conditions followed involving diazotization, alkylation, halogenation and 39 by oxidation with DBU/CCl4. condensation . Miyake et al. (2010) revised the structure of Kandemir et al.40 developed 5-(7-indolyl) oxazole Almazole D by constructing this molecule through and 2,5-di(7-indolyl) oxazoles from 7-formylindole 836 INDIAN J. CHEM., SEC B, JULY 2016

allo-Ile

Val O Leu H N O O O H NH HN O N Ph Ph HO NH N H O N O O O Ile N N N O N N N N N O O O O

O Val O H Ala O N N H NH O NH HO Ile N N O N O O O

Figure 3 — 2,4-Concatenated oxazoles

CH3 N O COOH N O O N O H O 14 MeO 13 MeO Cl O OMe O H N AlCl3 N POCl3 O OMe O 16 Me 15 Me

Scheme VI 17, its carbonyl protection with trimethylsilylnitrile A robust approach to synthesize substituted trailed the oxidation reduction sequence to afford 18 esters of oxazoles, thiazoles, imidazoles and diethyl and 19, respectively (Scheme VII). The combination pyrazine 2,5-dicarboxylates was reported. The two of 19 with different acylating agents produced 20a step methodology involving the C-formylation and and 20b after phosphorylation. cyclization of glycine ethyl ester hydrochloride An extremely modest process for di- and using Lawesson’s reagent with triphenyl phosphene tri-substituted oxazoles under metal free conditions resulted in targeted thiazoles and oxazoles via bromination and debromination of N-acylated respectively44. amino acid was developed41. The methyl esters of Sperry et al. have analyzed Diazonamide A N-acyldehydroaminobutyric acid and N-acyldehydro- (Figure 4) natural product by retrosynthetic strategy. phenylalanines gave the corresponding substituted Adopting a multistep approach, they proposed a oxazoles in high to moderate yields while under the biomimetic route to hetrocyclic core. A viable route same conditions, N-acyldehydroalanines failed to give involving the oxidative biomimetic cyclization by the corresponding oxazoles42. Synthesis of DDQ for tri and tetra peptides of tyrosine, valine, trisubstituted oxazoles 22a and symmetrical tryptamine and tryptophane, resulted in the direct bisoxazoles 22b was achieved through cyclization of synthesis of indole bisoxazole core of Diazonamide A45. corresponding diamides of N-acyl amino acid A library of highly effective anti-tuberculosis derivatives followed by oxidation with oxazole and oxazoline templates were derived from trifluoromethanesulfonic anhydride (Scheme VIII)43. threonine or serine in a three step process. In vitro and

GHANI et al.: 1,3-OXAZOLES AND BENZOXAZOLES 837

OMe OMe R R1 1

TMSCN R R2 2 N MeO N DDQ, dioxane MeO H H NC O H O 18 17

OMe R1 OMe R1 R2 H2, Pd/C (CH3CO)2O R2 MeO N N H MeO POCl3 H O O N NH2 20a 19

OMe OMe R1 R1

R2 R2 MeO N MeO H

Cl3C O O N Et3N, MeCN H MeO N POCl3 R2

OMe R1 20b

Scheme VII

O O O Ph Tf O, Et N MeO O OMe 2 3 OMe N NH MeO O Ph 21a 22a

H Ph N (CH ) O Ph Ph 2 n O Tf2O, Et3N N N O HN (CH ) MeO O OMe 2 n MeO O O OMe 21b 22b Ph Scheme VIII in vivo screening proved competency of oxazoles over oxazolines (Scheme IX)18. Cl HN N N During research on Telomestatin, Charalambidou A B Cl O O O prepared 2,4 linked bis and tris oxazoles from HN C 46 E NH protected serine derivatives through various steps . HO D An archive of thiazoles and oxazoles with structural O F G H NH variation at 2 and 5 positions was obtained by reacting O α-amido-β-ketoesters, an intermediate from dual acylation of a protected glycine, with Lawesson’s 47 Figure 4 — Diazonamide A reagent or dehydration, respectively . One pot 838 INDIAN J. CHEM., SEC B, JULY 2016

protocol was established and compared with two step of different catalytic systems like idosobenzene- method to fabricate 5-oxazolacetonitriles and trifloromethane sulfonic acid and idosobenzene- 5-oxazolacetates 27. The reaction sequence comprised bistrifloromethane sulfonyl imide to link various nitriles of cyclodehydration of N-acylamino acids 26 via with mono and dicarbonyl compounds furnished highly diisopropylcarbodiimide (DIC) followed by Wittig substituted oxazoles in a single step3. Vinyl sulfonamide olefination to achieve 5-oxazolacetate (Scheme X)48. based regioselective synthesis was presented for oxazole A facile synthesis of 5-(3-indolyl) oxazoles was analogues with out ring oxidation51. carried out by converting N-protected 3-acetyl-1- Microwave mediated novel (hydroxymethyl)oxa benzenesulfonyl indole 28 to hydroxyl (tosyloxy) and thiazole analogues from 3-oxetanone along with iodobenzene followed by amination of acyl group to complete computational and synthetic analysis were afford 29. Finally, the cyclodehydration by p-toluene explored52. sulfonic acid and deprotection of 29 subsequently 49 resulted in target molecule 30 (Scheme XI) . Oxazoles from oximes Compound 30 was also synthesized by using One step dirhodium (II) acetate promoted synthetic [hydroxy(2,4-dinitrobenzenesulfonyloxy) iodo]benzene strategy for 4-styryl-5-methoxy oxazoles was trailed and found advantageous due to easy handling, from oximes and styryl diazoacetate with diverse circumventing toxic metal and better yield50. Treatment functionalities53 (Scheme XII).

OH O O Oxalyl chloride OBn OH N R H R1 L-serine-OBn, DIPEA 1 O 23 R 24 R2 2 O OBn DAST N O R1 DBU, BrCCl3 25 R2

Scheme IX

O COOH COOEt O R1 N R2 Ph3P=CHCOOEt, DIC H R1 N R2 26 27

Scheme X

R R HN N O O O O C6H5I(OH)OTs PTSA

HMTA NaOH, EtOH-H2O N RCOCl N N SO C H 2 6 5 SO2C6H5 H 28 29 30

Scheme XI

Ar N HO 2 N N Rh2(OAc)4 O Ph CO Me 2 Ar Ph 32 OMe 31 33

Scheme XII

GHANI et al.: 1,3-OXAZOLES AND BENZOXAZOLES 839

Twenty new derivatives of 2,4,5-tri-substituted The 2-substituted benzoxazoles were prepared oxazoles 36 were constructed under optimal microwave and evaluated against various microbial strains and irradiation through N,O-acylation and cyclodehydration showed broad spectrum of activity. The of oximes swiftly. In vitro anti-proliferative evaluation comparative QSAR studies of new compounds were of all new compounds against PC-3 (human prostate also accomplished to test growth inhibitory cancer) and A431 (human epidermoid carcinoma) activity56. Heterocyclic multi-substituted oxazoles revealed maximum potential (Scheme XIII)16. were obtained from various aldehydes and The 1,3 disubstituted oxazoles were designed and evaluated for in vitro antimicrobial activity57. synthesized for in vivo anti-hyperglycemic, lipid Hydrazones 42 from substituted formyl chromones lowering and in vitro anti-diabetic screening by PTP- were treated with alcoholic potash to yield 1B assay54. Multistep synthesis of a series of 2-aryl- 1-(3,4-diflorophenyl-4-substituted-2-hydroxybenzoyl- naphthol[1,2-d] oxazole analogues 41 was executed 1H-pyrazoles 43. The oxime formation was and evaluated for cholesterol, triglyceride, lipid lowering continued to Beckman rearrangement to produce activity and protein tyrosine phosphatase-IB inhibition fluorine containing pyrazolyl benzooxazoles 44 potential. In vivo antidiabetic evaluation of new oxazoles exposing most promising antimicrobial activity, showed its promising activity (Scheme XIV)55. (Scheme XV)58.

CH3 N OMe OMe MeO OMe MeO OMe Br2, R1SH, Et3N MeO OMe R2 O N OMe NH2OH.HCl R O S 1 34 O 35 N SR1 36 OH

Scheme XIII

HO OH OH O BF3 NH2OH.HCl OH Ac2O COOH 37 38 39 AcO OR

NOCOCH3 N C5H5N OH O

41 40

Scheme XIV

R F 1 R1 R2 O F R OH F KOH, HCl 2 N N N F R3 N R H 3 O 42 O 43 R1 N O F NH OH.HCl N 2 R2 N F POCl3 44 R 3

Scheme XV 840 INDIAN J. CHEM., SEC B, JULY 2016

Oxazoles from intramolecular cyclization of amines Perner et al.68 put forward many innovative mono and Conversion of N-benzyl bis aryloxime ethers 45 to di-substituted-2-arylamino oxazole derivatives by two 2-arylbenzoxazoles 46 via copper (II) mediated methods given below. These novel compounds were cascade of C-H functionality and C-N/C-O bond transient receptor potential vanilloid 1 antagonists formation under oxygen free conditions was reported (Scheme XVIII). 59,60 (Scheme XVI) . A proficient silver promoted one step method for Two component intermolecular cyclization 2,4-disubstituted and 2,4,5-trisubstituted oxazoles was 61 Oxazoles established from amides established . Intramolecular iron-catalyzed O-arylation A facile synthesis of oxazolyl methylacetate of 2-haloanilines in presence of 2,2,6,6-tetramethyl- derivatives 54a was demonstrated via oxidative 3,5-heptanedione furnished benzoxazole derivatives 62 cycloisomerization of propargylamide 53 by successfully . phenyliodine (III) diacetate or hexafluoroisopropanol Iodine promoted cyclization of commercial aromatic 69 63 as oxidants . Oxazoles with unsaturated side chains aldehydes yielded disubstituted oxazoles . Dess-Martin 54b were also described by the same researcher. They periodinane mediated cyclization of phenolic azomethines 64 exploit oxypalladation induced cycloisomerisation of 47 to obtain pure 48 (Scheme XVII) was experimented . propargyl amides with allyl ethyl carbonates by Two distinctive routes to achieve 2-substituted Pd2(dba)3, IPr.HCl.Cy3P and Cs2CO3 in methyl nitrile benzoxazoles or 3-substituted benzisoxazoles from as catalytic systems with the subsequent reductive o-hydroxyaryl N-H ketimines via N-chloro imine elimination with variable yields (Scheme XIX)70. intermediate were presented. The key reaction was NaOCl facilitated Beckmann-type readjustment of An elegant transformation of acyl cyanides 55 into imine to benzoxazole and N-O bond formation to oxazoles 56 through dipolar cycloaddition of benzisoxazole65. Potent arylpiperazinylalkylamines diazomalonic esters was described (Scheme XX). These substituted oxazoles were synthesized by convergent Ph PIDA O OR synthetic process and biologically tested against α1G 66 N (Gav 3.1)T-type calcium channel . O-Acylations of ester functionalities followed by Wittig reactions HN 54a 67 Ph furnished trisubstituted oxazoles chemoselectively . O O Ph EtO2C O 53 R Ar R N Cu(OTf)2, O2 N Pd2(dba)3 N Ar 54b O O

45 46 Scheme XIX Scheme XVI OCH3 O H3CO2C N C(CO CH ) OH 2 2 3 2 O O CN N DMP R R Ar Rh2(OAc)4 N Ar N 55 56 O 47 48

Scheme XVII Scheme XX

Method A Br CF3 Ar O N CS O PPh3, 1,4-dioxane HN Ar N 49 CF3 52a 50 Method B H CF3

O TosCH(R4)NC, K2CO3 O 52b CF3 N 51

Scheme XVIII

GHANI et al.: 1,3-OXAZOLES AND BENZOXAZOLES 841

multicomponent condensations readily provide complex Intermolecular bond between enamines and heterocyclic scaffolds with outstanding applications71. different carboxylic acids, together with N-protected Substituted amide 57 was irradiated with different amino acids by using iodosobenzene as an oxidant haloketones 58 in presence of AgSbF6 in microwave. was established. Thus functionalized β-acyloxy Bromo and iodo acetophenones gave excellent yield enamines were transformed into oxazole through of oxazoles 59, while α-chloro and α-mesylate keto cyclodehydration by conventional method78. derivatives provided low yield and no reaction Bastug et al. explored benzooxazole, benzothiazole respectively (Scheme XXI)72. and benzimidazole derivatives by combining The stereoselective production of alkylidene o-substituted anilines with esters79. 2-Acetyl benzofuran oxazoles, oxazoles, and 1,3-oxazines from N-propargyl 63 was selected to form various derivatives of carboxamides by utilizing gold (I) or (III) catalysts and benzofuran oxazole 64 via bromo acetyl benzofuran. various alkynes as reactants was accomplished73. Targeted compounds were also evaluated for 80 Acetylenic amides cyclization via ZnI2 and FeCl3 antibacterial activity (Scheme XXIII) . fabricated 2-oxazoline and 2-oxazoles in high Treatment of substituted primary amides 65 with 74 yields . A unique and effective combination of 2,3-dibromopropene under the influence of Cs2CO3 ultrasonic radiation and deep eutectic solvents for furnished a variety of 2-aryl-5-alkyl substituted 81 oxazoles synthesis was pioneered. The phenacyl oxazoles 66a in single step (Scheme XXIV) . The bromide and phenyl urea precursors joined variety of oxazoles 66b was depicted by tandem one sonochemically, proved cutting edge in terms of pot cycloisomerisation of propargylic alcohols with 82 reaction time, yield and energy consumption as amides 65 using p-toluenesulfonic acid monohydrate . 75 compared to conventional methods . Br Catalyst free synthesis of oxazole analogues from Br O R cyclization of α-haloketone with urea in presence of N 76 Cs2CO3 reusable non-ionic liquid PEG 400 was reported . O 66a

Three step synthesis of novel oxazoles Schiff bases RNH2 and antimicrobial activities were executed. The steps 65 HO R' R' O involved formation of 2,4 disubstituted oxazole 62 Ar R N from aromatic aldehyde and hippuric acid 60 that was PTSA Ar 66b transformed to hydrazone leading to target molecule 62 77 using various aromatic aldehydes (Scheme XXII) . Scheme XXIV

O O R1 O AgSbF6 Br R2 R3 N R1 NH2 µW, 90°, 2-3 h R2 R 57 58 59 3

Scheme XXI

R1 R 1 R3 R2 OH HN NH NH (CH3CO)2O O 2 2 R2 R O N 4 R O ArCHO O ArCHO N N 60 61 R N O R 62

Scheme XXII

N NH2 Br2 O O O NH2CONH2 O 63 64

Scheme XXIII 842 INDIAN J. CHEM., SEC B, JULY 2016

Stokes et al. established the synthesis and structure wide but the hetroaryl attached with carbonyl group activity relationship (SAR) of oxazoles benzamides. produced correspondingly low yields while chalcone The oxazole benzamide chemotype (Figure 5) was having α-methyl substituent limited the scope of this prepared through different routes with various reaction88. substitutions and studied for antibacterial effects as Few aromatic analogues, 69 were also prepared by FtsZ inhibitor. Among all the compounds, using readily available starting materials 67 in one-pot 5-halosubstituted derivatives proved potent against operation under temperate domino oxidative 89 the mutant encoding the FtsZ G 196A amino acid. cyclization, mediated by t-BuO2H/I2 (Scheme XXV) . Besides this, the improvement in pharmacokinetic Amidation of vinyl halides promoted by copper, properties by considering the importance of following I2 mediated cyclization leads to various substitution pattern to pseudo benzylic position of substituted oxazoles and polyazols90. Another oxazoles, were also studied83. application of microwave mediated synthesis was Conventional and microwave assisted routes for 4- experimented in one pot domino acylation of 2- (3-indolyl)oxazole series were compared (Figure 6). bromoanilines from acyl chloride in Cs2CO3, 1,10- Among all the new oxazole motifs, three compounds phenanthroline, and copper iodide to afford showed promising cytotoxic activity due to the benzoxazoles 72 (Scheme XXVI)91. presence of benzyl group at indole nitrogen and Some novel 2-alkyl-5-aryl-substituted oxazoles were р-fluoro phenyl at C-2 of oxazole ring84. prepared by iodine catalyzed reaction of aryl methyl Fused oxazoles with antimicrobial screening were ketones, β-keto esters or styrenes with α-amino acids prepared through microwave assisted reaction of through decarboxylative domino reaction92. 4-phenyl piperidine 4,6-dione with α-bromoketones. Palladium catalyzed three components coupling of Although this protocol furnished oxazoles in excellent 2-amino phenols, aryl halides, and t-butyl isocyanide yield but the reaction scope is limited to α–bromoaceto in presence of Cs2CO3-toluene system afforded a phenone and α-bromoacetothiophenone85. range of benzoxazoles93. The synthesis of trisubstituted oxazoles through Oxazoles from amines Cano86 et al. developed 2,5-disubstituted oxazoles cascade formation of C–N and C–O bonds via Pd and in reasonable to excellent yields by reacting acyl Cu mediated oxidative cyclization provides a suitable process for the rapid synthesis of a range of 2,4,5- azides with 1-alkynes in the presence of 94 87 trisubstituted oxazoles in good yield . BrCu(NCMe)] BF4. Copper catalysed mild oxidative cyclization yielded polysubstituted oxazole O O R2 derivatives 68. Liu further extended this work using R1 chalcones as substrate to provide 2,5-diaryl oxazoles. R1 R2 O O N The scope of substrate for this reaction was relatively Cu(OAc)2.H2O, I2 Ar' 68 R1 Ar' NH2 O F N 67 Ar R O 2 Ar H N O O 2 N t -BuOOH, I2 69 F Ar'

Figure 5 — Oxazole benzamide chemotype Scheme XXV

NH N R1 N N O N O O

Cl N N R CH3 Cl

Figure 6 — Oxazoles with promising bioactivity

GHANI et al.: 1,3-OXAZOLES AND BENZOXAZOLES 843

H2N CuI, Cs CO O R' 2 3 R-COCl R' R' Br 15 min N 70 71 72

Scheme XXVI

O O R PdCl2(PPh3)2 O H N R Cl 2 Ar Cl CuI N 76 77 78 O 79 PTSA.H2O Ar

Scheme XXVIII

O Z O Z O O O Z

N N N

O O O O H N N O Ph Z = O n Z R O

Figure 7 — Aryl substituted oxazoles

Cl benzoyl chlorides were reacted with 2-fluoro-5- Cl nitroaniline in presence of potassium carbonate at NH2 O 99 N Ph 130◦ C via nucleophilic acyl substitution . O N N OH One-pot amidation-coupling-cycloisomerization 73 O Ph 75 was initiated from amidation of propargylamine 77, 74 followed by cross-coupling with acid chloride to afford substituted oxazol-5-ylethanones 79 Scheme XXVII (Scheme XXVIII)100. Investigations on two and three steps synthesis of The preparation of new N-(4-phenylthiazol-2-yl)- tri substituted oxazoles were done. In two step one- substituted benzo[d]thiazole-, thiazolo[4,5-b] pyridine-, pot procedure, in situ generated propargyl amides thiazolo[5,4-b]pyridine- and benzo[d]oxazole-2- were catalyzed by gold to propargyl amines while in carboximidamides, motivated by aquatic topsentines three step reaction the acid chlorides produced in situ and nortopsentines was reported. Different were reacted with propargyl amine preceding the aminopyridines aminophenols and o-halogenated 95 AuCl3 to afford a variety of target moieties . anilines were condensed with 4,5-dichloro-1,2,3- With reusable o-benzenedisulfonimide catalyst, the dithiazolium chloride providing the corresponding reaction among 2-amino-thiophenol, 2-aminophenol, aryliminodithiazoles as intermediate. Then copper o-phenylenediamine with various o-esters or mediated cyclization of aryliminodithiazoles gave aldehydes provided benzo fused azoles96. Two step thiazolo[4,5-b]- and thiazolo [5,4-b]-pyridines alkali promoted cyclization of N-sulfonyl benzo[d]oxazoles, benzo[d]thiazoles carbonitriles propargylamides via 1,4-sulfonyl migration efficiently which were further treated with substituted gave 5-sulfonylmethyl oxazoles involving allenes as 4-phenylthiazol-2-amines to provide twenty seven the key intermediates97. A catalyst free approach for novel polyaromatic carboximidamides in good benzothiazole and benzoxazole 75 was adopted by yields101. using 2-acylpyridazine-3(2H)-ones 74 as acyl source Three-components one-pot preparation of aryl- and 2-amino benzene thiole 2-amino phenol 73 substituted 5-(3-indolyl) oxazoles (Figure 7) was (Scheme XXVII)98. based on microwave induced MCR approach, The 5-nitrobenzoxazloes were obtained efficiently involving Sonogashira coupling, cycloisomerization under solvent free conditions. For this different and ultimate Fischer indole synthesis102. 844 INDIAN J. CHEM., SEC B, JULY 2016

A domino oxidative cyclization process to condensing aldehydes 80 with serine 81 via assemble 2,5-disubstituted oxazole derivatives was oxazolidine intermediate. Mild conditions were demonstrated in metal and peroxide free, I2 promoted required for this method as it did not require conditions103. This dual sp3 C-H functionalization intermediate purification due to the use of aldehydes approach was explored by using series of aryl methyl as a starting material rather than the methods using ketone and a group of various benzyl amines having carboxylic acids as reactant (Scheme XXIX)108. phenyl iodide and phenyl glyoxal as intermediates. A Effect of substituents on yield and reaction one pot synthesis of 2,4,5-trisubstituted oxazoles by conditions were explored by environmentally benign tandem reaction of a vinyl imino phosphorane with protocol for oxidation of 2-oxazolines-4-carboxamides/ acyl chlorides was also explored104. carboxylates to corresponding oxazoles 84. The same Economical formation of 2-substituted oxazoles methodology was also employed to synthesize a key and 2-imidazolines was provided by using intermediate for SC ααδ9 the phosphatase inhibitor 109 multicomponent approach among amines, ketones or (CDC25) as anticancer agent (Scheme XXX) . aldehydes and esters or α-acidic isocyano amides105. Highly proficient fragment-assembling approach 3-Oxazoline-4-carboxylates were oxidized to for oxazoles starting from aryl acetaldehydes and oxazole-4-carboxylates and derivatized to 4-keto- amines was explained110. A variety of 2,4- oxazole analogues utilizing grignard reagents106. A disubstituted naphth[2,1-d]-oxazol-5-ols 86 were new anti-inflammatory benzoxazole was formulated prepared from 3-substituted-2-amino1,4- by condensation of aromatic aldehydes with naphthoquinones 85 and substituted aldehydes in methyl-2-(2-aminothiazol-5-ylamino)benzo[d]oxazole- presence of HBr whereas H2SO4 produced 1,4- 5- carboxylate (Figure 8) by Ampati et al.17 naphthaquinone, other than oxazole. Ring opening of Fabrication of chiral 2-(substituted-hydroxyl)-3- oxazole to N-acyl-2-amino-1,4-naphthoquinone was (benzo[d]oxazol-5-yl) propanoic acid (Figure 9) also experimented through cerium (IV) ammonium analogues was achieved by structural modification in nitrate and bistrifloroacetoxy iodobenzene mediated 3-(4-hydroxyphenyl) propanoic acid skeleton107. oxidation (Scheme XXXI)111. Comprehensive structure activity relationship and Fabrication of 2-arylnaphtho[2,3-d]oxazole-4,9- antimicrobial activity of this molecule was also dione derivatives by the action of benzoyl chloride explored. analogs with 2-amino-3-bromo-1,4-naphthoquinone A direct method for the synthesis of 2,4- was demonstrated and evaluated for anticancer disubstituted oxazoles 82 was presented by activity on human prostate cells112.

HO R O MgSO4 O N RH BrCCl3, DBU H2N CO2Me 80 81 82 CO2Me

Scheme XXIX

R S N Ar R3 1 O COOR2 RCOOH, RCN/R1CHO H3CO2C N N HO N R3 NH NH2 O O 83 COOR2 84

Figure 8 — Methyl-2-(2-(4-(dimethylamino) benzylideneamino) thiazol-5-ylamino) benzo[d] oxazole-5-carboxylate Scheme XXX

O OH COOR2 R1O ∗ R1 R1 R2CHO, HBr

O NH2 N N O O N 85 86 R O 2

Figure 9 — Representative structure for substituted chiral oxazole Scheme XXXI

GHANI et al.: 1,3-OXAZOLES AND BENZOXAZOLES 845

R The efficient preparation of substituted R' Ph PAuNTf O R 3 anthraquinones and ring fusion into anthra[2,3- NC R' 87 88 Oxidant N d]oxazole-2-thione-5,10-dione derivatives was 89 described, and all the compounds were subjected for cytotoxicity against PC-3 cancer cell lines113. A Scheme XXXII variety of aliphatic and hetroaromatic carboxylic acids were reacted with 2-amino phenol and 2-amino OH R thiophenol in microwave, to accomplish 2-substituted 1 O NO benzoxazoles 5 and benzothiazoles 6 with Lawesson’s 2 R1 R 114 N reagent as effective promoter . 91a MeO OMe In Oxazoles from cyanide MeO R Two step palladium mediated route for 2,5- 90 O 115 disubstituted oxazoles and single step iodoarene Ph Ph O catalyzed pathway for substituted aryl oxazoles from NO2 R alkyl aryl ketones in trifluoromethanesulfonic acid N 116 91b was accounted . Moreover, new series of 2,4,5- trisubstituted oxazoles by using versatile aryl alkyl ketones, iodoarene and m-chloroperbenzoic acid was Scheme XXXIII 117 also established . N R R1 R1 R3 Gold catalyzed highly regioselective process was 3 PhIO N O adopted for 2,4,5-(hetero)aryl substituted oxazoles R2 92 93 R2 94 from unsymmetrical internal alkynes via 118 intermolecular cyclization . A novel synthetic Scheme XXXIV approach initiating from indole proceeded through O iodization, N-protection, Sonogashira coupling and RX, K2CO3 R' intermolecular alkyne oxidation steps generated α- SOTCN N R'CHO 95 oxacarbine which after gold catalysis yielded R 119 96 5-(3-indolyl) oxazoles . [2+2+1] Annulation of nitrile and terminal alkyne Scheme XXXV yielded 2,5-disubstituted oxazoles. This procedure involved an intermolecular cyclization of gold this reaction123. A facile synthetic application for anti- carbene, generated from oxidation of alkyne and inflammatory drug was presented by assembling 2,4- nitrile (Scheme XXXII)120. disubstituted and 2,4,5-trisubstituted oxazoles 94 via Nickel catalyzed cross-coupling of organo-zinc metal free [2+2+1] annulation of nitriles 92, alkynes reagents with 2-methylthio-oxazoles furnished 2 and 93 and oxygen regioselectively (Scheme XXXIV)124. 121 2,5-disubstituted oxazoles . This method was One pot Van Leusen oxazole approach by improved by one pot synthesis of chemoselective 2,5- consuming various aldehydes, tosylmethyl isocyanide disubstituted unsymmetrical oxazoles and complementary 36 and aliphatic halides in ionic liquids led to 4,5- to existing cyclodehydration approaches. disubstituted oxazoles 38 (Scheme XXXV)125. A reaction of 1-aryl-2-nitroethanone or 2- Oxazole and pyrrole 3-arylsulfonyl/3-carbethoxy nitrophenols with suitable orthoesters 90 as coupling D- and L-2-deoxyribosides were synthesized via reagent in presence of indium afforded oxazoles 91b TosMIC addition/cyclization126. The association of and benzoxazoles 92a, correspondingly. The oxone and iodoarene to elaborate metal free one pot mechanism involved one pot reduction-prompted synthesis of 2-alkyl, 5-aryl- and 2,4-disubstituted-5- intermolecular hetrocyclization of nitroso anion with aryl-oxazoles was investigated by reaction of aryl and immediate neighboring group (Scheme XXXIII)122. alkyl ketones with alkyl nitrile127. An efficient one pot The scope of metal free decarboxylative cyclization route (Scheme XXXVI) was accessed for of 2-bromoacetophenone and a variety of α-amino 2,5-disubstituted oxazoles 98. The reaction proceeded acids to polysubstituted oxazoles was investigated and via in situ isocyanides generation from cyanide salts, explored t-butyl hydroperoxide as the best oxidant for triethyl benzyl ammonium chloride128. 846 INDIAN J. CHEM., SEC B, JULY 2016

Convergent multistep synthesis of 2,4-linked arylglyoxal 110 and 2,4-dimethoxy benzylamine 108 trioxazoles 103 was proposed from oxazole ester 101 to assemble intermediate N-acyl-α-amino ketone via cyclisation to oxazolone intermediate (Scheme XXXIX). The subsequent debenzylation and (Scheme XXXVII). Over three steps the oxazolones cyclization of intermediate corresponded to trisubstituted were transformed to bisoxazol 102 which after oxazole analogues in considerable yield131. Niegishi cross coupling with mono oxazole furnished Synthesis, in vivo activity, structure activity trioxazole fragment129. relationship and metabolic profile were described for A facile synthesis of trisubstituted oxazoles a series of triazolopyridine based oxazole132. Two through gold catalyzed three component domino strategies to generate potent oxazole derivative of reaction was achieved. The synthetic utility of 2-amino thiazole (Figure 10) having high affinity for reaction was investigated by decarboxylation and 1,2 phosphoinositide-3-kinase (PI3K gamma) were migration reaction to yield vinyl and allyl substituted adopted. The synthesis executed via aza Wittig oxazoles (Scheme XXXVIII)130. olefination followed by hydrolysis and deprotection. Ugi/Robinson-Gabriel methodology was optimized The second approach comprised of reduction, to obtain oxazoles 112. Different carboxylic acids 109 coupling with acid and finally dehydration yielded the and several isonitriles 111 were subjected with target molecules133.

AgCN, KCN, TEBAC cat. R1 O O N N R1 Br R2 N S O 97 R COCl N R1 2 H 98

Scheme XXXVI Figure 10 — Substituted oxazole as phosphoinositide-3-kinase inhibitor O O OEt OO O OEt DBU NH4OH O O N CN O (COCl)2 N N O 99 100 101 CH2N2 102

O O Tf2O N N O OEt O O N EtO N 103

O ZnCl Pd(PPh ) 3 4

Scheme XXXVII

t-Bu O R [Au(salen)]PF6 t-Bu R Ph Cl N NBn N O 104 105 106 107 Ph

Scheme XXXVIII

MeO OMe O R1 COOH N HN R2 R O R2 1 Ar O NC O H 108 NH2 109 Ar 110 111 112

Scheme XXXIX

GHANI et al.: 1,3-OXAZOLES AND BENZOXAZOLES 847

Coupling of acyl chloride with isocyanide to obtain of oxazole and benzooxazole moieties with regio and 2,5-disubstituted oxazoles, avoiding 4,5-disubstituted stereospecificity also resulted in highly functioalized products by the use of Schollkopf conditions was oxazoles146-149. experimented. This method provides significant base- Simultaneously, C-H arylation of oxazole hetrocycles induced chemoselectivity in isocyanide chemistry134. via aryl bromide150 or iodide151 and carboxylation under Zhanga et al.135 put forward elegant synthesis metal free conditions was studied152. Alternatively, (Scheme XXXX) and photophysical properties of oxazole analogues are also achieved by the coupling of diversely substituted oxazole nucleus. This ring was 2-amino-1,3 oxazoles with chloro hetrocycles under mainly functionalized with electron accepting catalytic conditions153, two stage polyoxazole formation moieties. involving TBS-iodine exchange and Suzuki Miyaura Substituted 1,3-oxazole 117 and thiazoles were coupling154. The same substrate reacts with secondary prepared from alkyl, aryl, heteroaryl and 4-substituted alkyl halides using bis [2-(N,N-dimethyl amino) ethyl aryl amides and thioamides with substituted phenacyl ether to afford coresponding derivatives155. Amination of bromide (Scheme XXXXI). Thiazole and aryl moiety benzooxazoles with different amines was reported via with 2-alkyl/hetro aryl substitution in relation with copper catalyzed oxidation156, using iodine in aqeous t- p-bromo/chloro groups contribute significantly towards butyl hydroperoxide157 tetra-butyl ammonium iodide in 136 bactericidal potential than 1,3-oxazole analogues . aqeous hydrogen peroxide and transition metal free Solvent free microwave conditions for oxthiocyanates methods158. condensation with different anilines were elaborated to A new series of 4-substituted-2-(2´-hydroxyphenyl) 137 prepare 6-substituted-N-arylbenzo[d]oxazol-2-amines . benzoxazoles was constructed by modifying substituted phenyl oxazoles and also evaluated as Structure modifications of oxazole nucleus starving efficient anticancer agents159. Coupling of oxazoles for functionalized oxazoles with diarylmethyl carbonates in presence of PdCl2 Several synthetic protocols have been established to (MeCN)2/PPhCy2 as catalyst fabricated hetroarene synthesize different oxazole derivatives. Some of these containing triarylmethanes160. approaches involved microwave mediated preparation The exploration of diversified oxazoles towards of oxazole and benzoxazole exhibiting analgesic synthesis and pharmacological efficacy encompassed activity138, derivatives of oxazoles with activity against in vitro PPAR agonistic potential and in vivo Cannabinoid receptors139, Pd/Cu-mediated arylation of hypoglycemic, hypolipidemic, antitubercular, oxazoles with aryl halide140. Palladium catalyzed antibacterial, anti-inflammatory activity, while Suzuki cross coupling with C-2 alkylation of glycine substituted oxazoles in conjugation with 2-iodooxazole regioselectively was also reported141. hydroxycinnamic acid motifs afforded antioxidant Furthermore, the amination, alkoxylation, Suzuki- activity161-165. Synthesis of benzo[d] oxazole-4,7- Miyaura and Migita-Stille coupling of 5-bromooxazole142, dione derivatives having antifungal activity166 and homocoupling of oxazole-4-carboxylates were carried phenyl oxazole with in vitro cervical and breast out to obtain bis 5,5´-oxazole-4,4´-dicarboxylic oxazole cancer cells proficiency along with in vivo screening derivatives143. Arylation144,145, alkenylation, alkynylation of zebrafish embryos was unvailed by Dulla et al167. R In vitro anti-inflammatory action was best shown by O O O CHO HCl N azomethines of aryl oxazoles when diclofenac sodium was the reference standard168. Zn O R N HO Benzoxazole containing analogues have been 113 115 114 recognized as having high potential for showing various biological activities like antidepressant, Scheme XXXX antimicrobial, analgesic, anti-inflammatory and 169 Silica gel G-sulphuric acid R anticancer . Biaryl substituted oxazoles, imidazoles N R' RCN O and lower molecular weight thiazole carboxamides 116 O were very potent for peripherally sodium channel 117 R' 170 Br blockers . Novel oxazole derivatives were developed to conceal photophysical properties and proved new

Scheme XXXXI derivatives to exihibit more antifungal potential over 848 INDIAN J. CHEM., SEC B, JULY 2016

antibacterial171. Cyclocondensation of oxa and thiazol Synthetic methodology starting from primary α- analogues with thioglycolic acid was carried out to amino acid for oxazole provides a new path to utilize discover antibacterial potential in comparison with the benefits of iodine. Decarboxylative cyclization ampicillin and ciprofloxacin as standards172. was put forwarded that was initiated by the attack of Amido sulfonamido methane linked bisoxazoles, iodine. A molecule of carbondioxide was eliminated thiazoles and imidazoles with excellent antimicrobial from radical intermediate which further produced an and anticancer potential were reported by imine. Subsequent intramolecular type nucleophilic Premakumari173. A group of benzothiazole/benzoxazole- addition followed by oxidation yielded the required 2,3-dihydrobenzo[b][1,4] dioxine derivatives synthesized oxazole moiety (Route 4). from 2-(piperidine-4-yl)-benzo[d]thiazole/oxazoles Silver (I) salt catalysts promote an extensive range revealed high affinities for the 5-HT1A and 5-HT2A of reactions with improved yield. Amide and α- receptors with striking antidepressant-like activity174. halopyruvate underwent dehydrative cyclization via Ag+ activated α-halo group (pathway A) or activated Mechanistic perceptions leading to oxazoles carbonyl group (pathway B). By this mechanism, Following is the role of accelerating agents and α-halo keto derivatives proved to be very promising metal catalysts in the successful execution of oxazole potential building blocks for oxazole synthesis so this ring. Efficient procedures have been adopted to construct and improve the yield of targeted nucleus. N R1 Phenyliodine (III) diacetate (PIDA) is a very famous R O Ar O oxidant in metal based oxidative addition of nucleophile H R to alkyne functionality. Here propargylamide undergoes Ar 1 oxidative cycloisomerization in the presence of PIDA R N R1 H to yield derivatives of oxazole acetate (Route 1). 2,4,5-Trisubstituted oxazoles have been prepared HO Ar OH R from alkyl aryl ketone very conveniently. Oxone is Ar 1 RCN H responsible for the oxidation of iodoarene to R1 aryliodonium species that further reacted with ketone Ar ArI to give corresponding β-keto iodonium species. In the O final step nitrile make connection with β-keto OH iodonium compound to furnish oxazole (Route 2). ArI Herein, one pot synthesis of benzoxazole has been ArI TfO reported using intermolecular heterocyclization approach catalysed by indium (Route 3). Nitro compound was transformed into aniline molecule via nitroso species that 2KHSO KHSO K SO further reacted to give an imidate intermediate. In next 2KHSO5 KHSO4 K2SO4 4 4 2 4 step, hydroxyl group attacked the neighbouring imidate to TfOH form the ring structure. Aromatization was achieved by Route 2 — Proposed mechanism showing the role of iodoarene the removal of methanol. for oxazole nucleus118

OAc H OAc I OAc N AcOH N H Ph OAc OAc HN R1 R1 O I O I R2 Ph Ph R1 O R2 R2 AcOH

N AcOH N R1 R1 OAc O I O Ph PhI R R2 2

Route 1 — PIDA accelerated mechanism of oxazole synthesis67

GHANI et al.: 1,3-OXAZOLES AND BENZOXAZOLES 849

is an extension of substrate scope in the field of Reaction is initiated by the attractions of activated oxazole fabrication (Route 5). N-acyl iminium compound to metal acetylidine Gold salen complex is involved in different leading to amide formation. Loss of benzyl chloride is concentration in catalytic cycle of propargyl amide. in connection with the synthesis of oxazole because it

OMe MeO R H OH OH OH OH In/AcOH OMe O O O H NO NH N 2 2 R N R H H

-H

O proton -MeOH O OH H OH R transfer O O O N N R N -H H N R R H H

Route 3 — Indium mediated synthesis of benzoxazole113

I 1/2I2 Ph COOH Ph COO -CO Ph O O 2 O NH + NH NH Ph -H Ph Ph

O -H+

Ph Ph Ph + Ph O O O HO H OH N NH N -H+ N Ph Ph Ph Ph

Route 4 — Plausible mechanism involving iodine for oxazole ring construction114

O R1 O R NH O NH2 R 1 2 A X 2 B R NH R2 R2 1 2 O X X O O Ag Ag

B R1 H O R1 O NH 2 O X O NH O X R2 R2 R N OH R2 1

-H2O

O R2 N R1

Route 5 — Silver mediated oxazole synthesis70 850 INDIAN J. CHEM., SEC B, JULY 2016

preserves the catalytic behavior of gold. Finally, amides, amines and oximes furnish this five member isomerization is followed by proto-demetallation heterocyclic motif. Moreover, intermolecular resulting in the five membered ring (Route 6). approaches and three component reactions are well Deep eutectic solvents offer unique properties known for this scaffold. Our objectives to highlight whenever is employed for organic synthesis. This different synthetic approaches adopted for oxazole, to cutting edge methodology uses choline chloride and drag researchers for its production on modern aspects urea that build up attractions for reaction substrates. where deep eutectic solvents and sonication energy is This frame work increased the compatibility of the core of interest. However, mechanistic insights reagents; substituted amide and phenacyl bromide for clearly demonstrate the role of supporting agents like each other, hence efficiently furnished novel oxazole catalytic metals, etc. Reviewing this material would derivatives (Route 7)73 be rewarding to explore its untouched pharmacological activities and turn the focus of Conclusion chemists to develop novel versatility on oxazole. This review focuses on all different synthetic methodologies for 1,3-oxazole and benzoxazole Acknowledgement nucleus starting from 2007 till now, and also provides Authors are obliged to Higher Education a glimpse on its biological activity. Mainly Commission of Pakistan for financially supporting intramolecular cyclization of appropriately substituted this document.

N N Cl O + O M + M H O NBn

Cl H

H + + M / H O Ph N

N N Cl- O H N H + + H/ M O H+/M+ O Ph N O

N N +H Au O O - PF6

Route 6 — Mechanism proposing gold metal activity for the preparation of oxazole121

R R R H H -O N H -HBr H O N N N O O R N H R1 O 1 O Cl OH H Br O H H N N R R H H H -H2O O N N O R R H 1 O 1 O N R1 H

Route 7 — Mechanistic perception based on DES role in synthesis of oxazole73

GHANI et al.: 1,3-OXAZOLES AND BENZOXAZOLES 851

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