Search tips
Search criteria 


Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Synlett. Author manuscript; available in PMC 2010 December 1.
Published in final edited form as:
Synlett. 2009 December 22; 2010(4): 591–594.
doi:  10.1055/s-0029-1219374
PMCID: PMC2902884

Methodology for the Synthesis of Substituted 1,3-Oxazoles


The halogen dance isomerization is a facile and preparatively effective pathway for the synthesis of 2,4,5-trisubstituted-1,3-oxazoles.

Keywords: oxazoles, halogen dance rearrangement, alkylation

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,1 phorboxazoles A and B,2 diazonamides A and B,3 rhizopodin,4 telomestatin,5 and 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.7 These structural features have inspired wide-spread inclusion of substituted 1,3-oxazoles in medicinal chemistry, and particularly in the design of peptidomimetics. The proliferation 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.8 Studies 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 (Scheme 1).

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.17,18 Strangeland 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), 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 of Table 1) affording 67% to 80% yields of highly functionalized 2,4,5-trisubstituted-1,3-oxazoles.22

Table 1
The preparation of 4-bromo-5-substituted-2-(phenylthio)oxazole 2

In summary, our studies have shown that the halogen dance isomerization is a synthetically viable process which can be used to rapidly develop molecular complexity in the preparation of 2,4,5-trisubstituted-1,3-oxazoles. Selective replacement reactions of the 2-phenylthio and 4-bromo substituents of our products will enhance the generality and scope of our observations. Applications for the development of this chemistry in natural product synthesis is currently underway in our laboratories.


We acknowledge the support of Indiana University and partial support of the National Institutes of Health (GM042897).


1. Ichiba T, Yoshida WY, Scheuer PJ, Higa T, Gravalos DG. J. Am. Chem. Soc. 1991;113:3173–3174.
2. Searle PA, Molinski TF. J. Am. Chem. Soc. 1995;117:8126–8131.
3. For structure revision of diazonamide A: Li J, Burgett AWG, Esser L, Amezcua C, Harran PG. Angew. Chem. Int. Ed. 2001;40:4770–4773. [PubMed]
4. (a) Hagelueken G, Albrecht SC, Steinmetz H, Jansen R, Heinz DW, Kalesse M, Schubert W-D. Angew. Chem. Int. Ed. 2008;48:595–598. [PubMed] (b) For recent isolation of hemi-phorboxazole A: Dalisay DS, Molinski TF. Org. Lett. 2009;11:1967–1970. [PubMed]
5. Shin-ya K, Wierzba K, Matsuo K, Ohtani T, Yamada Y, Furihata K, Hayakawa Y, Seto H. J. Am. Chem. Soc. 2001;123:1262–1263. [PubMed]
6. (a) Rosener JA, Scheuer PJ. J. Am. Chem. Soc. 1986;108:846–847. (b) Dalisay DS, Rogers EW, Edison AS, Molinski TF. J. Nat. Prod. 2009;72:732–738. [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;66:247–250. [PubMed] (c) Kohno J, Kameda N, Nisho M, Kinumaki A, Komatsubara S. J. Antibiot. 1996;49:1063–1065. [PubMed]
8. (a) Phillips AJ, Uto Y, Wipf P, Reno MJ, Williams DR. Org. Lett. 2000;2:1165–1168. [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;121:1303–1305.
9. (a) Besselièvre F, Piguel S, Mahuteau-Betzer F, Grierson DS. Org. Lett. 2008;10:4029–4032. [PubMed] (b) Flegeau EF, Popkin ME, Greaney MF. Org. Lett. 2008;10:2717–2720. [PubMed] (c) Hodgetts KJ, Kershaw MT. Org. Lett. 2002;4:2905–2907. [PubMed] (d) Smith AB, III, Minbiole KP, Freeze S. Synlett. 2001:1739–1742.
10. Hämmerle J, Spina M, Schnürch M, Mihovilovic MD, Stanetty P. Synthesis. 2008:3099–3107.
11. For leading references: (a) Vedejs E, Luchetta LM. J. Org. Chem. 1999;64:1011–1014. [PubMed] (b) Whitney SE, Rickborn B. J. Org. Chem. 1991;56:3058–3063.
12. Williams DR, McClymont EL. Tetrahedron Lett. 1993;34:7705–7708.
13. Whisler MC, MacNeil S, Sneickus V, Beak P. Angew. Chem. Int. Ed. 2004;43:2206–2225. [PubMed]
14. Williams DR, Brooks DA, Meyer KG. Tetrahedron Lett. 1998;39:8023–8026.
15. Meyers AI, Lawson JP. Tetrahedron Lett. 1981;22:3163–3166.
16. Lee K, Counceller CM, Stambuli JP. Org. Lett. 2009;11:1457–1459. [PubMed]
17. For reviews of the halogen dance reaction, see: (a) Bunnett JF. Acc. Chem. Res. 1972;5:139–147. (b) Marzi E, Bigi A, Schlosser M. Eur. J. Org. Chem. 2001:1371–1376.
18. For a leading reference: Stanetty P, Schnürch M, Mereiter K, Mihovilovic MD. J. Org. Chem. 2005;70:567–574. [PubMed]
19. Strangeland EL, Sammakia T. J. Org. Chem. 2004;69:2381–2385. [PubMed]
20. Stanetty P, Spina M, Mihovilovic MD. Synlett. 2005:1433–1434.
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 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 NaHCO3, 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.