Oxazoles as Substrates

There are several recent reports of this transformation but only that affording 

1-arylpyrazines appears to be of practical utility, as illustrated in the following examples  

2-p-Mcthoxyphcnyl-4-phenyl-4,5-dihydro-5-oxazolonc (59) gave, among other separable products, 2,3-bis(/ methoxyphcnyl)-5,6-diphenylpyrazine (60) (2,5-diphcnyl-2//-tctrazole, PhOMe, reflux, 5 h 31% the formation of this byproduct did not involve the tetrazole, of which an equivalent amount was recovered).325 

3-(2-Anilinoethyl)-2-oxazolidinone hydrochloride (61) gave 1-phenylpiperazine hydrochloride (63) directly (neat, N2, 170°C, 4 h 88%) or via N-(2-anili-noethyl)-Ar-(2-bromoethyl)amine (62) [AcOH—30% HBr, 20°C, 4 days crude (62), EtOH, reflux, 4 days 85%] other 1-aryl- and 1-alkylpiper-azines were made by both methods.1493 

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In the photochemical isomerization of isoxazoles, we have evidence for the presence of the azirine as the intermediate of this reaction. The azirine is stable and it is the actual first photoproduct of the reaction, as in the reaction of r-butylfuran derivatives. The fact that it is able to interconvert both photochemically and thermally into the oxazole could be an accident. In the case of 3,5-diphenylisoxazole, the cleavage of the O—N bond should be nearly concerted with N—C4 bond formation (8IBCJ1293) nevertheless, the formation of the biradical intermediate cannot be excluded. The results of calculations are in agreement with the formation of the azirine [9911(50)1115]. The excited singlet state can convert into a Dewar isomer or into the triplet state. The conversion into the triplet state is favored, allowing the formation of the biradical intermediate. The same results [99H(50)1115] were obtained using as substrate 3-phenyl-5-methylisoxazole (68ACR353) and... 

The highly reactive intermediate isoimides of the type 209 have actually been obtained as reaction products when fused-ring oxazoles are employed as substrates. For example, the photosensitized autoxidation of the phenyl-substituted oxazole 211 in methanol yields the iV-benzoylimino anhydride (212 ).126-362 Further studies on the reaction of oxazoles with singlet oxygen... 

Hajjem and Baccar used cyanomethylimidates as substrates for addition of organozinc reagents to prepare (3-ketoimidates that cyclized to 2,5-disubstituted-oxazoles as shown in Scheme 1.95. For example, addition of an alkenylzinc... 

In the search for bioactive sphingosine 1-phosphate (SIP) receptor ligands, a series of 2-amino-2-heterocyclic propanols (242-245) have been synthesized. These molecules were discovered as substrates of human sphingosine kinases (SPHKl and SPHK2). The oxazole-derived structure was the most active for human SPHK2. Imidazole analogues were less active substrates for SPHKs, but more potent and selective agonists of the SI PI receptor. 

Vasylyev and Alper [55] accidentally discovered new access to hexahydropyrrolo [2,l-b]oxazoles during the chromatographic work-up of the hydroformylation products with AT-allyl-oxazolidines as substrates (Scheme 5.163). Through deuter-ation experiments and NMR spectroscopy, a mechanism was established where cyclization under discharge of formaldehyde takes place under the catalytic... 

In summary, the most efficient catalysts for substrates 36-40 are the Ser-PHOX and ThrePHOX complexes 46 and 12, as well as the recently reported oxazole-phosphinite complexes 14. 

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]. 

As shown in previous sections, NHCs promote acyl transfer in transesterification reactions. In a similar manner, O C acyl transfer can be achieved with substrates such as 351 in the presence of 0.9 mol% of triazolium pre-catalyst 353 and KHMDS (Scheme 53). Moderate yields are obtained by varying substitution of the oxazole from R = Me, Ph, t-Bu, and t-Pr [171], Deprotonation of the triazolium salt followed by nucleophilic addition to the carbonate moiety of the oxazole results in enolate intermediate LXXXIII and activated carboxylate LXXXIV. Enolate addition and regeneration of the active catalyst provides quaternary stereocenters 352. 

In the present case, for example, isomer 1 is an excellent alternative to flavin as a flavin reductase substrate. The Km for isomer 1 is 1.6 juM. This value compares favorably with that for PQQ, which has a K, of 2 juM. However, attempted use of isomer 1 in protection against reoxygenation injury would likely result in complete conversion to the noncatalytic and probably genotoxic oxazole before isomer 1 had any chance to protect against reoxygenation injury. Thus, as isomer 1 attempted to deaminate oxidatively simple amines and amino acids encountered in the tissue, the deamination intermediates would be converted at unacceptable rates into genotoxic oxazoles. 

To a large extent, similar methods are used for the preparation of thiazole-, dihydrothiazole-, and thiazolidine-based peptides as presented in Section 11.2.3 for the preparation of the corresponding oxazole- and dihydrooxazole-based peptides. However, the oxidation of dihydrothiazole and thiazolidines to the aromatic heterocycles is considerably more facile than for the analogous oxygen-containing substrates. 

Control experiment indicated that template effect (in the presence of different metal salts) [108] was not operating for this transformation. The presence of NH function in 86 that could potentially form a H-bond with oxazole ring, thus preorganizing the cyclization precursor [109], was not an obligation. Indeed, compound 86 (R = H) and 87 (R = Et, Fig. 2) was obtained in essentially identical yield. Aliphatic diamines are suitable substrates, as cyclophane 88 and 89 can be prepared in reasonable yield. It is interesting to note that a 47% yield of 89 meant 88% yield per chemical bond created, including the macrocyclization step. 

The carbonylation reaction is also applicable to other five-membered N-hetero-cycles, such as thiazoles, oxazoles, and pyrazoles [36], The reactivity of the substrates increases with increasing pfCa values of the conjugate acids of the N-heterocycles according to the series imidazole (pfCj 7.85) > thiazole (pfCa 3.37) > oxazole (pKa 2.91) > pyrazole (pKa 2.09). This indicates that the coordination of the substrates by the sp nitrogen to the ruthenium center is the key step in the carbonylation of C-H bonds in N-heterocycles. 

Examples of cycloadditions with oxazole substrates that lead to products other than furans are also known. 4-Substituted oxazole 73 has been used in an intramolecular Diels-Alder reaction <2004TL6471> with an alkene to afford a pyridyl cycloadduct 74 in good yields en route to the synthesis of a Rauwolfm alkaloid, (—)-suaveoline. This reaction required refluxing xylene with l,5-diazabicyclo[4.3.0]non-5-ene (DBN) as an additive (Scheme 13). 

The antiviral marine natural product, (-)-hennoxazole A, was synthesized in the laboratory of F. Yokokawa." The highly functionalized tetrahydropyranyl ring moiety was prepared by the sequence of a Mukaiyama aldol reaction, cheiation-controiied 1,3-syn reduction, Wacker oxidation, and an acid catalyzed intramolecular ketalization. The terminal olefin functionality was oxidized by the modified Wacker oxidation, which utilized Cu(OAc)2 as a co-oxidant. Interestingly, a similar terminal alkene substrate, which had an oxazole moiety, failed to undergo oxidation to the corresponding methyl ketone under a variety of conditions. 

Using the N-(co-alkynyl)-N-alkyl-a-isocyanoacetamide 41 as a polyfunctional substrate, three-component synthesis of the azaindoline 42 was developed. By simply heating a toluene solution of 41, a primary amine and an aldehyde afforded tricyclic compound 42 in good to excellent yield [32]. A possible reaction sequence that accounted for the formation of 42 is depicted in Scheme 5.13. The sequence involved (a) a three-component synthesis of oxazole 43, (b) intramolecular D-A cycloaddition... 

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