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INTRODUCTION:-

Medicinal chemistry concerns with the discovery, development, interpretation and the identification of mechanism

of action of biologically active compounds at the molecular level. An important aspect of medicinal chemistry has

been to establish a relationship between chemical structure and pharmacological activity. Several of the important

compound contain heterocyclic rings, e.g. heterocyclic ring are present in most of the member of vitamin B-

complex , most of the alkaloids, antibiotics, chlorophyll, haemoglobin ,other plant pigment, aminoacids ,dyes,

drugs, enzymes, the genetic material, DNA etc..Oxazoleis the parent compound for a vast class of

heterocyclicaromaticorganic compounds. These are azoleswith an oxygen and a nitrogen separated by one carbon.

Oxazoles are aromatic compoundsbut less so than the thiazoles. Oxazole is a weak base; its conjugate acidhas a

pKaof 0.8, compared to 7 for imidazole. Isoxazole is an azolewith an oxygen atom next to the nitrogen. Isoxazole

rings are found in some natural products, such as ibotenic acid. Isoxazoles also form the basis for a number of drugs,

including the COX-2 inhibitor valdecoxib(Bextra).some of the physical as well as the chemical properties of the

oxazole & isoxazole nucleus are described

Various physical & chemical properties of oxazole & isoxazole are similar (table-1) but substitution on different

position on the nucleus of oxazole & isoxazole gives different derivative with different pharmacological

effects.Oxazole does not occur in nature & thus does not play any part any part in fundamental metabolism as doimidazole & thiazole.Still most of the oxazole derivative are under clinical trial or under investigation for treatment

of disease like cancer , diabetic. some derivative of oxazole derivative are used as plateletaggregation inhibitor,

calcium imaging, NSAID, wavelength shifter, treatment of absence seizure , antibiotic activity. Similarly the

isoxazole derivative possess antibiotic activity, treatment of T.B.,U.T.I ,treatment of cancer, anti-viral

,N.S.A.I.D.,Treatment of severe rheumatoid arthritisand psoriatic arthritis.etc.

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Given below is a brief account of various alterations conducted on oxazole & isoxazole ring containing few

importent marketed drug,dugs under clinical trial and their associated biological activities in table-2 & table-3

respectively.

Table-2

Methodology for the Synthesis of Substituted 1,3-Oxazoles

In recent years, structural elucidation studies of biologically significant natural products have frequently

incorporated novel 1,3-oxazole ring systems within complex molecular architectures. Numerous examples include

hennoxazole A,1phorboxazoles A and B,2diazonamides A and B,3rhizopodin,4telomestatin,5and the ulapualides.6

In addition, 1,3-oxazole moieties are commonly displayed within depsipeptides as a result of oxidative

cyclodehydrations of serine and threonine residues.7These structural features have inspired wide-spread inclusion of

substituted 1,3-oxazoles in medicinal chemistry, and particularly in the design of peptidomimetics. The proliferation

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of complex structures for challenging syntheses has ignited renewed interests in the development of effective

methodologies toward substituted oxazoles. We have previously described an oxidative cyclodehydration route as a

general strategy for the de novo preparation of 2,4-disubstituted 1,3-oxazoles.8Studies toward the elaboration of the

oxazole nucleus have reported cross-coupling reactions of alkenylation and arylation at C-29 as well as Stille

reactions of 2-phenyl-1,3-oxazoles.10

Efforts for elaboration of the oxazole nucleus can be greatly facilitated by site-selective formation of a reactive

carbanion. Kinetic deprotonation of the C-2 hydrogen of the parent oxazole provides access to a ring-closed

carbanion as well as the ring-opened isonitrile enolate.11 C-Acylations of the enolate produce 4,5-disubstituted

oxazoles via the Cornforth rearrangement.12 Examples of site-selective ring metalations via complex-induced

proximity-effects13 (CIPE) have been recorded in [2,4]-bisoxazoles14 and for 2-methyl-1,3-oxazole-4-carboxylic

acid.15 Furthermore, Stambuli and coworkers have recently described the selective C-5 deprotonation of 2-

methylthio-1,3-oxazole leading to the production of 2,5-disubstituted oxazoles.16

In this letter, we describe the kinetic C-4 deprotonation of 5-bromo-2-phenylthio-1,3-oxazole (1a) which initially

leads to the lithium species 1b. Upon warming to 0 C, anion 1b undergoes efficient isomerization to afford the

reactive 5-lithio-4-bromo-2-phenylthio-1,3-oxazole (2a). Reactions of 2a with a variety of electrophiles yield the

trisubstituted oxazoles 3. Transmetalation of the lithium species 2a provides the zinc reagent 2b for effective Negishi

cross-coupling processes to give products of alkenylation and arylation at the C-5 position

The nature of the isomerization which leads from the 5-bromo heterocycle 1a to yield the 4-bromo derivative 2a is

described as the halogen dance (HD) reaction. This base-induced migration has been studied in aromatic and

heteroaromatic systems.17,18Strangeland and Sammakia first demonstrated an example of the halogen dance in a 1,3-

thiazole system,19 and Stanetty and coworkers have recently published the only oxazole example of this halogen

migration in their studies of 5-bromo-2-phenyl-1,3-oxazole.20

In the course of our studies of 2,5- and 2,4-disubstituted oxazoles, we have found that the base-catalyzed halogen

exchange of 2-phenylthio-5-bromo-1,3-oxazole (1)21 is a facile process with considerable synthetic utility. Thus,

treatment of 1a with LDA at 78 C leads to deprotonation at C-4 providing 1b which subsequently undergoes rapid

halogen exchange with starting 1a. This process generates the intermediates 5 and 6 thereby facilitating a final

bromine transfer to produce the more stable lithium reagent 2a (Scheme 2). After stirring at 0 C (45 min), solutions

of 2a were cooled to 78 C for the introduction of various electrophiles. Upon warming to 22 C, reaction mixtures

were quenched and the products were purified by flash silica gel chromatography prior to full characterizations. A

survey of our results are complied in Table 1, and illustrate useful yields in a number of alkylation processes

including condensations with aldehydes and ketones (entries 5, 6, 7, 8, and 9 of Table 1). Our conditions permit

facile isomerization of the 5-bromo compound 1a to yield the corresponding 4-bromo-1,3-oxazole (Table 1, entry 1),

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which serves as an important precursor for the regiocontrolled synthesis of 2,4-disubstituted oxazoles. Additionally,

the regioselective introduction of 5-iodo, 5-stannyl, and 5-silyl functionality (Table 1, entries 2, 3, 4) advance new

opportunities for site-specific reactivity in these heterocycles. Our efforts have also recorded the transmetalation of

2a to provide 2b via the addition of anhydrous ZnBr2 in THF at 0 C. As a result, these studies provide for cross-

coupling reactions with aryl and alkenyl iodides (entries 10, 11, 12, and 13 ofTable 1) affording 67% to 80% yields

of highly functionalized 2,4,5-trisubstituted-1,3-oxazoles.22

References

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5. Shin-ya K, Wierzba K, Matsuo K, Ohtani T, Yamada Y, Furihata K, Hayakawa Y, Seto H. J. Am. Chem. Soc.

2001;123:12621263. [PubMed]

6. (a) Rosener JA, Scheuer PJ. J. Am. Chem. Soc. 1986;108:846847. (b) Dalisay DS, Rogers EW, Edison AS,

Molinski TF. J. Nat. Prod. 2009;72:732738. [PubMed]

7. For examples: (a) Kanoh K, Matsuo Y, Adachi K, Imagawa H, Nishizawa M, Shizuri Y J. Antibiot. 2005;58:289

292. [PubMed]

(b) Perez LJ, Faulkner DJ J. Nat. Prod. 2003;66:247250. [PubMed]

(c) Kohno J, Kameda N, Nisho M, Kinumaki A, Komatsubara S J. Antibiot. 1996;49:10631065. [PubMed]

8. (a) Phillips AJ, Uto Y, Wipf P, Reno MJ, Williams DR Org. Lett. 2000;2:11651168. [PubMed]

(b) For initial application of this methodology in the synthesis of hennoxazole A: Williams DR, Brooks DA,

Berliner MA J. Am. Chem. Soc. 1999;121:13031305.

9. (a) Besselivre F, Piguel S, Mahuteau-Betzer F, Grierson DS. Org. Lett. 2008;10:40294032. [PubMed] (b)Flegeau EF, Popkin ME, Greaney MF. Org. Lett. 2008;10:27172720. [PubMed] (c) Hodgetts KJ, Kershaw MT.

Org. Lett. 2002;4:29052907. [PubMed] (d) Smith AB, III, Minbiole KP, Freeze S. Synlett. 2001:17391742.

10. Hmmerle J, Spina M, Schnrch M, Mihovilovic MD, Stanetty P. Synthesis. 2008:30993107.

11. For leading references: (a) Vedejs E, Luchetta LM J. Org. Chem. 1999;64:10111014. [PubMed]

(b) Whitney SE, Rickborn B J. Org. Chem. 1991;56:30583063.

12. Williams DR, McClymont EL. Tetrahedron Lett. 1993;34:77057708.

13. Whisler MC, MacNeil S, Sneickus V, Beak P. Angew. Chem. Int. Ed. 2004;43:22062225. [PubMed]

14. Williams DR, Brooks DA, Meyer KG. Tetrahedron Lett. 1998;39:80238026.

15. Meyers AI, Lawson JP. Tetrahedron Lett. 1981;22:31633166.

16. Lee K, Counceller CM, Stambuli JP. Org. Lett. 2009;11:14571459. [PubMed]

17. For reviews of the halogen dance reaction, see: (a) Bunnett JF Acc. Chem. Res. 1972;5:139147.

(b) Marzi E, Bigi A, Schlosser M Eur. J. Org. Chem. 2001:13711376.

18. For a leading reference: Stanetty P, Schnrch M, Mereiter K, Mihovilovic MD J. Org. Chem. 2005;70:567574.

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19. Strangeland EL, Sammakia T. J. Org. Chem. 2004;69:23812385. [PubMed]

20. Stanetty P, Spina M, Mihovilovic MD. Synlett. 2005:14331434.

21. The preparation of starting oxazole 1 was accomplished as follows: A methylene chloride solution of 2-

phenylthio-1,3-oxazole (1.0 equiv) and anhydrous Et3N (1.5 equiv) was stirred at 0 and bromine (1.5 equiv) in

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methylene chloride (1:1 by volume) was introduced by slow dropwise addition. The reaction mixture was allowed to

slowly warm to 22 C and stirring was continued overnight. The reaction was quenched with aq saturated NaHCO 3,

and was extracted with CH2Cl2. Organic phases were combined and washed with aq sodium bisulfite and then dried

over anhydrous Na2SO4. Evaporation of solvent and flash silica gel chromatography (8:1 Hex:EtOAc) provided 5-

bromo-2-phenylthio-1,3-oxazole (75% yield).

22. Yields of Table 1 are provided for purified products which were characterized by proton and carbon NMR

spectroscopy, IR and HRMS analysis.

Preparation

Classical oxazole synthetic methods inorganic chemistryare

theRobinsonGabriel synthesisby dehydration of 2-acylaminoketones theFischer oxazole synthesisfrom cyanohydrins and aldehydes theBredereck reactionwith -haloketonesandformamide

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theVan Leusen reactionwith aldehydes andTosMICOther methods are reported in literature.

Oxazolines can also be obtained from cycloisomerization of certain propargyl amides. In one study[3]oxazoles were prepared via a one-pot synthesis consisting of the condensation ofpropargyl amine and

benzoyl chlorideto theamide, followed by aSonogashira couplingof the terminalalkyneend with another

equivalent of benzoylchloride, and concluding withp-toluenesulfonic acidcatalyzedcycloisomerization:

In one reported oxazole synthesis the reactants are anitro-substitutedbenzoyl chlorideand anisonitrile:[4][5]

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