Oxazoles intermolecular

An intermolecular version of a [4+2] cycloaddition-retrofragmentation of alkyne-oxazoles can be adapted to the synthesis of 2,3,4-trisubstituted furan in high regioselectivity if acetylenic aldehydes are used as starting materials. The product of this reaction is a pivotal intermediate for the synthesis of (-)-teubrevin G <00JA9324>. 

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... 

The alkylation of the G-H bonds occurs even in the CH=N moiety of five-membered heteroaromatic compounds such as thiazoles, benzimidazoles, and oxazoles (Equation (25)).26,26a This intermolecular alkylation without chelation assistance is very interesting. 

Palladium chemistry involving heterocycles has its unique characteristics stemming from the heterocycles inherently different structural and electronic properties in comparison to the corresponding carbocyclic aryl compounds. One example illustrating the striking difference in reactivity between a heteroarene and a carbocyclic arene is the heteroaryl Heck reaction (vide infra, see Section 1.4). We define a heteroaryl Heck reaction as an intermolecular or an intramolecular Heck reaction occurring onto a heteroaryl recipient. Intermolecular Heck reactions of carbocyclic arenes as the recipients are rare [12a-d], whereas heterocycles including thiophenes, furans, thiazoles, oxazoles, imidazoles, pyrroles and indoles, etc. are excellent substrates. For instance, the heteroaryl Heck reaction of 2-chloro-3,6-diethylpyrazine (1) and benzoxazole occurred at the C(2) position of benzoxazole to elaborate pyrazinylbenzoxazole 2 [12e]. 

One active field of research involving the Heck reaction is asymmetric Heck reactions (AHR). The objective is to achieve enantiomerically-enriched Heck products from racemic substrates using a catalytic amount of chiral ligands, making the process more practical and economical Although intermolecular Heck reactions that occurred onto carbocyclic arenes are rare, they readily take place onto many heterocycles including thiophenes, furans, thiazoles, oxazoles,... 

Aromatic acid chlorides and 2-(triphenylphosphoranylidenamino)cinna-mates (127) give rise to l,3-oxazol-5-ones (129), as shown in Scheme 51. After an intermolecular aza-Wittig reaction with 127, the ethoxy O attacks... 

The intermolecular Heck reactions of oxazoles and thiazoles with olefins are not too common. They are rarely high yielding since in several cases they are biased by dehalogenation. Due to this reason the olefination of these systems is usually achieved through Stille coupling with vinylstannanes. 

This may imply that the intermolecular coupling of various aryl halides with other heteroaromatic compounds may proceed. Indeed, it is now known that not only the special heteroaromatic halides but also usual aryl halides can react with a variety of five-membered aromatic heterocycles, including furans, thiophenes, and azole compounds such as M-substituted imidazoles, oxazoles, and thiazoles [133-137]. The arylation of azoles can be carried out using iodobenzoate immobilized on an insoluble polymer support [138]. Related intermolecular reactions of indole [139] and imidazole [140] derivatives have also been reported. 

The three 1,3-azoles, imidazole, thiazole and oxazole, are aU very stable compounds that do not autoxidise. Oxazole and thiazole are water-miscible liquids with pyridine-like odours. Imidazole, which is a solid at room temperature, and 1-methylimidazole are also water soluble, but are odourless. They boil at much higher temperatures (256 °C and 199 °C) than oxazole (69 °C) and thiazole (117 °C) this can be attributed to stronger dipolar association resulting from the very marked permanent charge separation in imidazoles (the dipole moment of imidazole is 5.6 D cf. oxazole, 1.4 D thiazole, 1.6 D) and for imidazole itself, in addition, extensive intermolecular hydrogen bonding. The dihydro- and tetrahydro-1,3-azoles are named imidazoline/imidazolidine, thiazoline/thiazolidine and oxazoline/oxazolidine. 

Intermolecular Alkyne Oxazole Diels-Alder Reactions... 

The autoassociation phenomena of oxazole and 2,4-dimethyloxazole have been studied by Meyer et al.sot A cryometric analysis of the inert solvent-oxazole binary system reveals the existence of intermolecular oxazole-oxazole type association. Data obtained with 2,4-dimethyloxazole indicate the importance of steric hindrance in this type of association.306 Oxazoles readily form stable complexes with metal salts of the general formula BMXs (where M is a bivalent metal cation).196 196 These are very useful in isolation and characterization of oxazoles. 

Imidazole, colourless crystals, mp 90°C, bp 256°C, is soluble in water and other protic solvents, but only sparingly soluble in aprotic solvents. Imidazoles have high melting and boiling points when compared to pyrrole, oxazole and thiazole because the imidazole molecule is a donor as well as an acceptor of hydrogen bonds, and only intermolecular hydrogen bridges can be formed. 

Examples of intermolecular cycloadditions of oxazoles with alkenes since 1985 include approaches to the ubiquitous analogs of the 3-hydroxypyridine pyridoxol, several applications in medicinal chemistry, and the first demonstrations of oxazole acting as a dienophile in [4 + 2] cycloadditions. 

TABLE 3.1. INTERMOLECULAR OXAZOLE-OLEFIN DIELS-ALDER REACTIONS... 

The azaphenanthrene alkaloid eupolauramine appeared to be an ideal target for exploring the applicability of an intramolecular Kondrat eva pyridine synthesis in the construction of natural products. Despite the fact that 2-phenyloxazoles are unreactive in intermolecular cycloadditions, the Diels-Alder reaction of oxazole-olefin 97 was expected to provide the tricyclic framework of eupolauramine... 

The intermolecular oxazole-olefin Diels-Alder reactions are summarized in Table 3.1, p. 431. 

TABLE 3.2 INTERMOLECULAR OXAZOLE-ALKYNE DIELS-ALDER REACTIONS, 445... 

TABLE 3.4 INTERMOLECULAR OXAZOLE-HETERODIENOPHILE DIELS-ALDER REACTIONS, 461... 

Vedejs utilized a Negishi reaction in synthesizing the core of aziridinomitosene A. The C5 position of a C2-substituted oxazole was lithiated and transmetalated with ZnCh. The 5-oxazolylzinc chloride was utilized in an intermolecular Negishi reaction with a vinyl triflate in 70% yield with no reported intramolecular reaction at the alkyl iodide. ... 

Ohta and co-workers carried out extensive studies on intermolecular arylation of various heterocycles (furan, thiophene, pyrrole, oxazole, thiazole, A-methylimi-dazole, benz[fe]oxazole, benzo[i>]furan, and benzo[ ]thiophene) with mainly chlo-ropyrazines as heteroaryl halides using Pd(PPh3)4 and AcOK [3]. 

This reaction has been extended to the translocation of the acyl group for indole derivatives. In addition, a chiral planar DMAP derivative has been developed and applied for the enantioselective rearrangement of 0-acylated azlactone and the same catalyst recently has been used for an intermolecular reaction to form 1,3-diketones. Moreover, 3-(2,2,2-triphenyl-1 -acetoxyethyl)-4-(dimethylamino) pyridine (TADMAP) has been applied as a chiral nucleophilic catalyst to catalyze the carboxyl migration of oxazolyl, furanyl, and benzofuranyl enol carbonates with good to excellent levels of enantioselec-tivity. The rearrangement for oxazole derivatives are particularly efficient for giving chiral lactams and lactones. ... 

The oxazole-based click compound 107 was proposed as a G quadruplex ligand. It was particularly selective for those telomeric sequences that form multiple quadruplex motifs. MD simulations suggested a structural model in which the ligand is sandwiched between tandem quadruplexes and involved in several intermolecular interactions (14CC15202). 

In addition to intermolecular carbonylations, there are intramolecular reactions that allow for the synthesis of various heterocycles. As a prime example, the intramolecular alkoxy- or aminocarbonylation (cyclocarbonylation) of hydroxyl-or amino-substituted aryl/vinyl halides enables the synthesis of lactones, lactams, oxazoles, thiazoles, imidazoles, etc. [229]. 

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