Furans oxazoles

Heterocycles diazoles, furan, oxazoles, pyrrole (all-atom) FKBP12 inhibitors... 

The ionization energy of imidazole was calculated to be 8.78 eV. The removed electron is derived from the HOMO t3. From a comparison with the value of 8.23 eV for pyrrole, it follows that the pyridinelike N-atom reduces the HOMO energy and thereby stabilizes the r-system. This also applies to the furan-oxazole and thiophene-thiazole system. 

The particularly mild conditions of Passerini reactions, and the corresponding broad functional group tolerance, has meant that many reactive functionalities can remain unprotected on the component substrates and then utilized in a secondary reaction as a tandem or domino reaction sequence. Notably, this facet has led to the extensive use of the Passerini reaction for the construction of numerous functionalized furans, oxazoles, tetrazoles, P-lactams, butenolides and other complex heterocycles. 

Because of space restrictions, we have decided to omit a discussion on catalytic cydoadditions, leading to furans, oxazoles, isoxazoles, imidazoles, pyrazoles, pyridines, and other cycloaddition approaches (e.g., [3-1-3], [3-t-2-l-l], and [2-I-2+1+1] to pyridines), but the reader is encouraged to consult the excellent review by Gulevich etal. [45]. 

In general, the solubility of heterocyclic compounds in water (Table 33) is enhanced by the possibility of hydrogen bonding. Pyridine-like nitrogen atoms facilitate this (compare benzene and pyridine). In the same way, oxazole is miscible with water, and isoxazole is very soluble, more so than furan. 

Oxazoles give acylamino ketones (158) by acid-catalyzed ring scission, although they are somewhat more stable than furans. The oxazole ring is also moderately stable to alkali (74AHCU7)99) as expected, reaction with hydroxide ions is facilitated by electron-with-drawing substituents and fused benzene rings. 

The 4- and 5-hydroxy-imidazoles, -oxazoles and -thiazoles (499, 501) and 4-hydroxy-pyrazoles, -isoxazoles and -isothiazoles (503) cannot tautomerize to an aromatic carbonyl form. However, tautomerism similar to that which occurs in hydroxy-furans, -thiophenes and -pyrroles is possible (499 500 503 504 501 502), as well as a zwitterionic... 

Modification of reaction schemes leading to furans, thiophenes and pyrroles by incorporation of a heteroatom into the substrate provides ready access to imidazoles, thiazoles, oxazoles, dithioles, oxathioles, etc. Incorporation of two heteroatoms into the substrates... 

A Hiickel model used for calculating aromaticity indicated that the isoxazole nucleus is considerably less aromatic than other five-membered heterocycles, including oxazole and furan. SCF calculations predicted that isoxazole is similar to oxazole. Experimental findings are somewhat difficult to correlate with calculations (79AHC(25)147). PRDDO calculations were compared with ab initio values and good agreement for the MO values was reported... 

In this section coverage follows the general order of Part I [93AHC (57)271] in that heterocycles fused to furan will precede those fused to thiophene and pyrrole fused oxazoles will precede fused thiazoles, etc. 

The diazotization of heteroaromatic amines is basically analogous to that of aromatic amines. Among the five-membered systems the amino-azoles (pyrroles, diazoles, triazoles, tetrazoles, oxazoles, isooxazoles, thia-, selena-, and dithiazoles) have all been diazotized. In general, diazotization in dilute mineral acid is possible, but diazotization in concentrated sulfuric acid (nitrosylsulfuric acid, see Sec. 2.2) or in organic solvents using an ester of nitrous acid (ethyl or isopentyl nitrite) is often preferable. Amino derivatives of aromatic heterocycles without ring nitrogen (furan and thiophene) can also be diazotized. 

Keywords furans, pyrroles, thiophenes, phospholes, oxazoles, pyrones, pyr-idones, oxazinones, high pressure... 

It should be mentioned that the Passerini reaction has also been used by Marcac-cini s group to prepare p-lactams [24], oxazoles [25], and furanes [26]. Natural products have also been accessed using this procedure as one of the key steps. The syntheses of azinomycin by Armstrong [27] and eurystatin A by Schmidt [28] represent two good examples of this procedure. 

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>. 

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,... 

Interestingly, the alkyne-oxazole Diels-Alder cycloaddition strategy provides a unique entry to some furyl stannanes [52]. Thus, thermolysis of bis(tributylstannyl)acetylene (50) and 4-phenyloxazole (51) led to a separable mixture of 3,4-bis(tributylstannyl)furan (52, 19% yield) and 3-tributylstannylfuran (53, 23% yield). 

Oxazoles and benzoxazoles are viable participants in the heteroaryl Heck reactions. In their monumental work published in 1992, Ohta and colleagues demonstrated that oxazoles and benzoxazoles, along with other rc-sufficient aromatic heterocycles such as furans, benzofurans, thiophenes, benzothiophenes, pyrroles, thiazole and imidazoles, are acceptable recipient partners for the heteroaryl Heck reactions of chloropyrazines [22b]. Therefore, treatment of 2-chloro-3,6-diethylpyrazine (27) with oxazole led to regioselective addition at C(5), giving rise to adduct 28. By contrast, a similar reaction between 2-chloro-3,6-diisobutylpyrazine (29) and benz[fc]oxazole took place at C(2) exclusively to afford pyrazinylbezoxazole 30. 

The aromaticity of isoxazole has been reviewed in terms of theoretical and structural studies,138 139 and the conclusion is that it is slightly less aromatic than oxazole and furan. 

The reaction of acylsilanes with acid chlorides in the presence of A1C13 leads to furans (Table 9.41) [45]. In these reactions an acyl cation initiates the addition with ensuing silyl migration yielding an intermediate vinyl cation. Attack of the carbonyl oxygen followed by proton loss affords the observed products (Scheme 9.16). An analogous reaction with nitrosyl fluoroborate provides a route to oxazoles (Table 9.42) [65]. The nitrosyl cation serves as the electrophile in this application. 

Similar to 136, furan 137 was also prepared via the oxazole route. Yun Yang, a student from Guangzhou Institute of Chemistry, thermolyzed oxazole 139 and bis(tri-n-butylstannyl)acetylene 155 in a sealed tube to afford a separable mixture... 

McDonald, N. A. and Jorgensen, W. L. (1998) Development of an all-atom force field for heterocycles. Properties of liquid pyrrole, furan, diazoles, and oxazoles. J. Phys. Chem. B 102, 8049-8059. 

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