2-Chlorooxazole

Like thiazole, oxazole is a jt-electron-excessive heterocycle. The electronegativity of the N-atom attracts electrons so that C(2) is partially electropositive and therefore susceptible to nucleophilic attack. However, electrophilic substitution of oxazoles takes place at the electron-rich position C(5) preferentially. More relevant to palladium chemistry, 2-halooxazoles or 2-halobenzoxazoles are prone to oxidative addition to Pd(0). Even 2-chlorooxazole and 2-chlorobenzoxazole are viable substrates for Pd-catalyzed reactions. 

Condensation of aryl halides with various active methylene compounds is readily promoted by catalytic action of palladium to give the corresponding arene derivatives containing a functionalized ethyl group [7]. Yamanaka et al. extended this chemistry to haloazoles including oxazoles, thiazoles and imidazoles [8]. Thus, in the presence of Pd(Ph3P)4,2-chlorooxazole was refluxed with phenylsulfonylacetonitrile and NaH to form 4,5-diphenyl-a-phenylsulfonyl-2-oxazoloacetonitrile, which existed predominantly as its enamine tautomer. In a similar fashion, 4-bromooxazole and 5-bromooxazole also were condensed with phenylsulfonylacetonitrile under the same conditions. 

Substituted oxazolo[4,5-Z ]pyridines 138 (and quinolines) were synthesised in high yields from zwitterion or hydroxyamidine derivatives 137, obtained by treatment of non-enolisable amides 136 with the complex base NaNH2-/-BuONa, via hetaryne intermediates. Intramolecular cyclization and NH3 elimination to give 138 were performed in dimethylacetamide by heating or microwave irradiation <03S2033>. Different approaches to oxazolo[4,5-c]quinoline-4(5/f)-ones from ethyl 2-chlorooxazole-4-carboxylate have also been described <03OL2911>. 

Aminooxazoles 58 have also been obtained from the corresponding 2-chlorooxazoles 57 by displacement with anilines to give products in modest to excellent yields (Equation 3) <2005JMC1610>. 

The readily available ethyl 2-chlorooxazole-4-carboxylate proved to be a versatile scaffold for the synthesis of 2,4-disubstituted oxazoles and 2,4,5-trisubstituted oxazoles. 

Disubstituted oxazole 26 was prepared from 2-chlorooxazole-4-ethylcarboxylate via the Suzuki coupling with phenylboronic acid [26]. The carboxylic functionality at C(4) of 26 could then be exploited by a variety of synthetic transformations. 

Maekawa er al. reported that a series of co-oxazolylalkanoic acid derivatives as antidiabetic agents, promoting the glucose-dependent secretion of insulin. (o-(5-Oxazolyl)alka-noates 27, the key intermediates for the synthesis of target compounds, were prepared via Suzuki coupling of substituted 2-chlorooxazole with phenylboronic acid [34]. 

Vinyloxazole-4-ethylcarboxylate (37) was prepared from 2-chlorooxazole-4-ethyl-... 

The Hantzch-Panek condensation of ethylpyruvate with acrylamide followed by treatment with trifluoroaceticanhydride (TFAA) provided 2-vinyloxazole-4-ethylcarboxylate 37 in good yield [57]. The Stille coupling of 2-chlorooxazole-4-ethylcarboxylate with vinyltrimetbylstannane also provided 2-vinyloxazole 37 [26]. The reactivity of 37 towards cycloaddition reactions with enone and coupling reactions with aryl halides were explored [57]. Heck reaction of vinyloxazole with p-iodoanisole gave the cinnamyl oxazole 97 in 71% yield [57]. 

Although oxazoles follow the pattern and lithiate at C-2, 4-substituted products are produced with some electrophiles this is explained by a ring opening of the anion, to produce an enolate, which after C-electrophilic attack, recloses. An estimate by NMR spectroscopy showed the ring-cleaved tautomer to dominate the equilibrium." Some electrophiles produce good yields of oxazole products reaction of lithi-ated oxazole with hexachloroethane produces 2-chlorooxazole in good yield." The open enolates can be... 

As detailed previously, Vedejs showed that trapping of 2-lithiooxazole with 1,2-diiodoethane yields 2-iodooxazole. Daugulis has demonstrated non-cryogenic conditions for the direct bromination of C2-unsubstituted oxazoles using dibromotetrafluoroethane as the electrophile. The Sandmeyer reaction can be utilized to prepare 2-chlorooxazoles from 2-aminooxazoles. Hexachloroethane can also be used as an electrophile for the direct chlorination of 2-lithiooxazole. The conversion of 2-oxazolones to 2-trifloyloxazoles is also possible however, 2-trifloyloxazoles decompose at high temperatures. ... 

In total synthesis papers, most reported Stille reactions involving oxazoles occur remotely to the oxazole ring. Most papers detailing direct Stille reaction of an oxazole ring are methodology papers. Williams showed that 2-phenylsulfonyl-5-stannyloxazole is a competent coupling partner with a vinyl iodide in a Stille reaction, and Taylor utilized a series of 2-chlorooxazoles as coupling partners for Stille reaction with... 

There are many examples of halogen at a 2-position undergoing nucleophilic displacement, for example 2-halothiazoles with sulfur nucleophiles (indeed, more rapidly than for 2-halopyridines), 2-halo-1-substituted imidazoles, and 2-chlorooxazoles with nitrogen nucleophiles. 

By using a sequence of regiocontrolled halogenation and palladium-catalyzed coupling reactions, the synthesis of variously substituted oxazoles from 2-chlorooxazole-4-carboxylate was accomplished. The methodology was applied to the synthesis of a series of 2,4-disubstituted, 2,5-disubstituted, and 2,4,5-trisubstituted oxazoles (Equation 37) [37]. 

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