Methodology for the Synthesis of Substituted 1,3-Oxazoles

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; alkylationIn 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-2 9 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-effects 13 (CIPE) have been recorded in [2,4]-bisoxazoles 14 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.16In 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 NIH-PA Author ManuscriptNegishi 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 ...

Efficient Suzuki and Stille Reactions for Regioselective Strategies of Incorporation of the 1,3-Oxazole Heterocycle: Mild Desulfonylation for the Synthesis of C-4 and C-5 Monosubstituted Oxazoles

“…11 Furthermore, we have shown that 5-bromo-2-(phenylthio)-1,3-oxazole ( 8) undergoes a facile base-induced isomerization, characterized as a halogen dance rearrangement to provide access to the 4-bromo-1,3-oxazole 11 (85%). 13 In this letter, we have described a survey of Suzuki and Stille cross-coupling reactions, which demonstrate the utility of these derivatives for a convenient general preparation of 2,5-and 2,4-disubstituted oxazoles. In addition, we have documented the use of sodium hydrosulfite for reductive desulfonylations to yield C-4 and C-5 monosubstituted 1,3-oxazoles.…”

“…However, the well-behaved carbanion from 7 (Scheme 3, R = SO 2 Ph, X = Li) facilitates convenient halogenation and stannylation reactions yielding 9 and 10 , respectively 11. Furthermore, we have shown that 5-bromo-2-(phenylthio)-1,3-oxazole ( 8 ) undergoes a facile base-induced isomerization, characterized as a halogen dance rearrangement to provide access to the 4-bromo-1,3-oxazole 11 (85%) 13. In this letter, we have described a survey of Suzuki and Stille cross-coupling reactions, which demonstrate the utility of these derivatives for a convenient general preparation of 2,5- and 2,4-disubstituted oxazoles.…”

Widely Exploited, Yet Unreported: Regiocontrolled Synthesis and the Suzuki–Miyaura Reactions of Bromooxazole Building Blocks

“…Among several known methods for the preparation of 4bromooxazoles, [2,4,30,32,35,[50][51][52][53] we have turned our attention to the LDA-mediated halogen dance reaction of 2-substituted 5bromooxazoles (Scheme 3). [54][55][56] Thus, the advantage of abovedescribed one-pot reaction sequence for the preparation 5bromooxazole (10) might be taken for the synthesis of the previously unknown 4-bromo derivative (11), if LDA-mediated halogen dance step would be added (Scheme 4). It is interesting to note that unlike 2-TIPS-5-bromoxazole (34), isomeric 2-TIPS-4-bromoxazole (35) could be isolated from the reaction mixture, and it was stable at r.t. Due to this reason, its chromatographic purification became possible, which gave the product 35 in 46 % yield.…”

Synthesis and Photooxidation of the Trisubstituted Oxazole Fragment of the Marine Natural Product Salarin C

“…Williams et al have shown that 4-bromo-5iodo-2-(phenylsulfanyl)oxazole can be accessed in a halogen dance reaction starting from easily accessible 5-bromo-2-(phenylsulfanyl)oxazole. 8 The sequence is believed to start by deprotonation at C4 followed by 1,2-migration of the halo substituent to the 4-position, placing the negative charge at C5. 9 In a similar manner, Stambuli et al accessed disubstituted 2-aryl-4-alkenyloxazoles after a halogen dance reaction starting from 2-(n-butylsulfanyl)-5-iodooxazole.…”

“…The 4-alkenyl side chain could be introduced in Pd-catalyzed cross coupling reaction. Williams et al have shown that 4-bromo-5-iodo-2-(phenylsulfanyl)­oxazole can be accessed in a halogen dance reaction starting from easily accessible 5-bromo-2-(phenylsulfanyl)­oxazole . The sequence is believed to start by deprotonation at C4 followed by 1,2-migration of the halo substituent to the 4-position, placing the negative charge at C5 .…”