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. Author manuscript; available in PMC: 2010 Dec 1.
Published in final edited form as: Synlett. 2009 Dec 22;2010(4):591–594. doi: 10.1055/s-0029-1219374

Methodology for the Synthesis of Substituted 1,3-Oxazoles

David R Williams 1,*, Liangfeng Fu 1
PMCID: PMC2902884  NIHMSID: NIHMS212665  PMID: 20640045

Abstract

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).

Scheme 1.

Scheme 1

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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

Scheme 2.

Scheme 2

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Table 1.

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

graphic file with name nihms212665t1.jpg
Entry Conditionsa Electrophile Product Yield (%)
1 A H2O graphic file with name nihms212665t2.jpg 88
2 A graphic file with name nihms212665t3.jpg graphic file with name nihms212665t4.jpg 87
3 A n-Bu3SnCl graphic file with name nihms212665t5.jpg 83
4 A TIPSOTf graphic file with name nihms212665t6.jpg 89
5 A graphic file with name nihms212665t7.jpg graphic file with name nihms212665t8.jpg 82
6 A HCHO graphic file with name nihms212665t9.jpg 72
7 A graphic file with name nihms212665t10.jpg graphic file with name nihms212665t11.jpg 79
8 A graphic file with name nihms212665t12.jpg graphic file with name nihms212665t13.jpg 74
9 B graphic file with name nihms212665t14.jpg graphic file with name nihms212665t15.jpg 87
10 C graphic file with name nihms212665t16.jpg graphic file with name nihms212665t17.jpg 80
11 C graphic file with name nihms212665t18.jpg graphic file with name nihms212665t19.jpg 67
12 C graphic file with name nihms212665t20.jpg graphic file with name nihms212665t21.jpg 72
13 C graphic file with name nihms212665t22.jpg graphic file with name nihms212665t23.jpg 77
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a

Condition A: A concentrated solution of 5-bromo-2-phenylthio-1,3-oxazole (1) (1.0 equiv) in THF was added dropwise into a freshly prepared solution of LDA (1.5 equiv) in THF at −78 °C. After stirring at −78 °C for 10 min, the mixture was warmed to 0 °C using an ice bath and maintained at 0 °C for 45 min. Upon cooling to −78 °C, THF solutions of electrophilic reagents (1.5 equiv) were introduced with continued stirring for 15 min. Reactions were then allowed to warm to 22 °C and were quenched with aq saturated NH4Cl. Extraction (ether), drying the organic extracts over MgSO4, and flash silica gel chromatography led to the purified products.

b

Condition B: Following the metalation of oxazole 1, anhydrous HMPA (10 equiv) was added at −78 °C. Alkyl iodide (1.5 equiv) in THF was then introduced at −78 °C and the reaction mixture was warmed to 22 °C with stirring overnight. Isolation and purification as described in Condition A.

c

Condition C: Following the metalation of oxazole 1 as previously described, anhydrous ZnBr2 (1.2 equiv) in THF was added at 0 °C, and the mixture was allowed to warm to 22 °C with continued stirring for 1 hr. A solution of aryl or alkenyl iodide (1.5 equiv) and Pd(PPh3)4 (10 mol%) in dry DMF was then added, and the reaction mixtures were stirred at 22 °C, or at 45 °C in the case of entry 12, for 18 to 24 hr. Isolation and purification as described in Condition A above.

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.

Acknowledgment

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

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