Oxazole metalation

The chemistry of the thiazoles does, of course, bear some similarity to that of the oxazoles. Metallated thiazoles and thiazole derivatives have found use, for example, both as carbonyl equivalents and masked acetaldehyde enolates. Additionally, as will be exemplified below, thiazole derivatives have served as catalysts for benzoin-type condensations, and they have provided access to a unique class of activated acid derivatives. 

Of course, the issue of chemoselectivity in oxazole metalation can be alleviated if one or more positions are blocked in the starting oxazole. When the C2 position is blocked, the next most acidic site is C5. C5-metalated oxazoles do not suffer from ring opening equilibrium the way C2-metalated oxazoles do. If both C2 and C5 are blocked, metalation occurs at C4. 

Intramolecular hydrogen transfer Intramolecular hydrogen transfer is found in anils, benzylpyridines, triazoles, oxazoles, metal dithizonates, and perimidinespirohexadienones... 

Addition to Aldehydes. The Vedejs oxazole metalation has often been applied in the addition of oxazoles to aldehydes. In order to avoid ring opening to the isonitrile, the oxazole is first complexed with borane, then reacted with BuLi to generate the 2-metalo nucleophile (eq 15). This has been applied in the synthesis of a-ketooxazole inhibitors, and angiotensin II (AT2)... 

This chapter is an attempt to present the important results of studies of the synthesis, reactivity, and physicochemical properties of this series of compounds. The subject was surveyed by Bulka (3) in 1963 and by Klayman and Gunther (4) in 1973. Unlike the oxazoles and thiazoles. there are few convenient preparative routes to the selenazoles. Furthermore, the selenium intermediates are difficult to synthesize and are often extremely toxic selenoamides tend to decompose rapidly depositing metallic selenium. This inconvenience can be alleviated by choice of suitable reaction conditions. Finally, the use of selenium compounds in preparative reactions is often complicated by the fragility of the cycle and the deposition of metallic selenium. 

Oxygen-containing azoles are readily reduced, usually with ring scission. Only acyclic products have been reported from the reductions with complex metal hydrides of oxazoles (e.g. 209 210), isoxazoles (e.g. 211 212), benzoxazoles (e.g. 213 214) and benzoxazolinones (e.g. 215, 216->214). Reductions of 1,2,4-oxadiazoles always involve ring scission. Lithium aluminum hydride breaks the C—O bond in the ring Scheme 19) 76AHC(20)65>. 

Under inversion of the configuration at sulfur, enantiomerically pure 4,5-dihydro-2-[(7 )-sulfinylmethyl)]oxazoles (e.g 2) are obtained from metalaled 4,5-dihydrooxazoles and (-)-menthyl (5,)-4-methylbenzenesulfinate31. 

Metalation of 4,5-dihydro-2-[(7 )-sulfinylmethyl]oxazoles (e.g., 2) with butyllithium at -90 C and reaction of the chiral azaenolates with aldehydes furnishes the hydroxyalkylated sulfinylox-azole derivatives 3 which are desulfurized to give the 4,5-dihydro-2-(2-hydroxyalkyl)oxazoles 4. The corresponding 3-hydroxy acids 5 are obtained by acidic hydrolysis in 60-85% overall yield and 26-53% ee31. 

Kitatani et al. found that tungsten(VI) chloride would catalyse the formation of a range of oxazoles from benzoyl(phenyl)diazomethane and nitriles (Scheme 17).<74TL1531, 77BCJ1647> The reaction with acetonitrile was studied with a range of other metal chlorides, but all proved less satisfactory than WCle. They attributed the catalytic nature of tungsten(Vl) chloride to both its Lewis acidity and the affinity of tungsten for carbenes. 

The mechanism of the condensation in Part D probably involves thioformylation of the metallated isocyanoacetate followed by intramolecular 1,1-addition of the tautomeric enethiol to the isonitrile. This thi2izole synthesis is analogous to the formation of oxazoles from acylation of metallated isonitriles with acid chlorides or anhydrides. " Interestingly, ethyl formate does not react with isocyanoacetate under the conditions of this procedure. Ethyl and methyl isocyanoacetate have been prepared in a similar manner by dehydration of the corresponding N-formylglycine esters with phosgene and trichloromethyl chloroformate, respectively. The phosphoryl chloride method described here was provided to the submitters by Professor U. Schollkopf and is based on the procedure of Bohme and Fuchs. The preparation of O-ethyl thioformate in Part C was developed from a report by Ohno, Koi/.uma, and Tsuchihaski. " ... 

Ru, Os, and Ir carbene complexes have been prepared from reactions of anionic or low-valent metal complexes with some organic salts or neutral compounds with highly ionic bonds. Oxidative addition of halothiazole and -oxazole species to IrCl(CO)(PMe2Ph)2 affords Ir(III) complexes which on protonation yield cationic carbenes (69), e.g.,... 

Analysis of intermolecular interactions in the crystal structures of oxime molecules has been used to answer that question. In all available complex structures with one central metal ion we found no coordinative bonds from the oxime oxygen to the metal, but exclusively coordination between the nitrogen atom and the metal ion (data were retrieved from the Cambridge Crystallographic Database [14]). In a comprehensive study Bohm et al. investigated complexes of oxazoles, methoxypyridines, and oxime ethers with water [15]. On the basis of interaction energies obtained... 

Transition metal-catalyzed reactions of ct-diazocarbonyl compounds proceed via electrophilic Fischer-type carbene complexes. Consequently, when cr-diazoketone 341 was treated, at room temperature, with catalytic amounts of [ RhiOAcbh, it gave the formation of a single NH insertion product, which was assigned to the enol stmcture 342. At room temperature, in both solid state and in solution, 342 tautomerizes to give the expected 1-oxoperhydropyr-rolo[l,2-c]oxazole derivative 343 (Scheme 50) <1997TA2001>. 

The least acidic of the three available position on oxazole is the 4-position, but even this can be lithiated under the appropriate conditions (86CRV845). Thus, while 2,5-diphenyloxazole gives a mixture of products on treatment with n-BuLi, clean metalation at C-4 can be achieved using LDA or KDA (86CRV845), or with 5-BuLi and a catalytic amount of LiTMP (Scheme 86)(91JOC3058). 

By analogy with oxazoles and N-substituted imidazoles, thiazoles and benzothiazoles unsubstituted at C-2 undergo direct metalation at that position, with sodium, lithium, or magnesium reagents (Scheme 91)[79MI1 ... 

Methoxycarbonyl-2-methyl-1,3-oxazole (3) is metalated exclusively at C5 with n-butyllithium. Selective functionalization at the methyl group of 3 can be achieved with N-bromosuccinimide to yield the 2-bromomethyl derivative 8. The latter affords a route to... 

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