Metalations oxazole

The synthesis of 2-acyloxazoles has always been a challenging task. Their synthesis through the use of metallated oxazole is troubled by its ring opened form (as an enolate isonitrile) which is predominant. A very useful new procedure for this synthetic approach is offered by the use of i-PrMgCl as a metallating reagent and a Weinreb amide 102 as the electrophile. This procedure was applied both to 5-(hetero)-aryl substituted oxazoles and unsubstituted oxazoles <07JOC5828>. 

Nucleophilic Attack at Hydrogen and Reactions of Metallated Oxazoles... 

The samarium(ll)-mediated Barbier reaction has been used as an alternative to the deprotonation chemistry to generate 2-alkyl-metallated oxazoles (Scheme 43). This reaction is very useful for the coupling of 2-iodomethyl oxazoles and aliphatic aldehydes. However, reactions with aromatic aldehydes gave mainly pinacol coupling products <20050L4099>. 

The synthesis of phorboxazole B has been accomplished in 27 linear steps [11] in an overall yield of 12.6%. The key fragment couplings include a metalated oxazole alkylation and an oxazole-stabilized Wittig olefination. 

This section details some recent examples of regioselective ring metalation and regioselective lateral metalation and subsequent functionalization. The examples were arbitrarily selected to demonstrate the versatility of such analogues. There is no attempt to include every metalated oxazole and the reader should consult the primary literature for additional examples. The synthesis and cross-coupling reactions of stannyloxazoles, silyloxazoles, and other organometallic oxazole analogues are discussed in Sections 1.4.8 and 1.4.9, respectively. 

In more specialized carbon NMR topics, a summary of assignments for 2,5-diaryloxazoles 190 has been published (Fig. 2.8). Girault and Perronnet give extensive spectral data for this class of compounds. NMR-based investigations of 2-metalated oxazoles 191 and their related anionic species have appeared (Fig. 2.9). ° ... 

Oxazoles are acidic at C2 with a theoretical pKg value of 21 Metalation is facile at C2 with strong bases. C2-metalated oxazoles are in equilibrium with their ring-opened isonitrile. Due to this equilibrium, C2-metalated oxazoles are nucleophilic at either C2 or C4, and care must be taken when quenching the C2-metalated oxazole to ensure proper chemoselectivity (see Section 6.3.3). Benzoxazoles are acidic at C2 like oxazoles (experimental pKa 24.8), and the metalated benzoxazole is also in equilibrium with its ring opened isonitrile. Isoxazoles, without a C-H group flanked by two heteroatoms, are acidic at the C5 position with a theoretical pKa value of 27 however, in practice, deprotonation with hydroxide occurs at C3 to give a ring-opened P-ketonitrile intermediate. All of these heterocycles can be deprotonated with metal amides or carbanion bases. 

As mentioned above, the heterocycles can be easily metalated with a variety of bases. The oxazole ring and the benzoxazole ring can be metalated at C2 with a variety of strong bases. The major limitation of metalated oxazoles and benzoxazoles is their equilibrium with an open chain p-alkoxynitrile (see Section 6.3.1). In the ring-closed form, the oxazole is nucleophilic at C2. In the open chain form, the anion is nucleophilic at C4. This dual reactivity of the oxazole anion can lead to undesired regiochemistry unless carefiilly monitored. 

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. 

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 ... 

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