Aldehydes 5-substituted oxazoles

The van Leusen reaction forms 5-substituted oxazoles through the reaction of p-tolylsulfonylmethyl isocyanide (1, TosMIC) with aldehydes in protic solvents at refluxing temperatures. Thus 5-phenyloxazole (2) is prepared in 91% yield by reacting equimolar quantities of TosMIC and benzaldehyde with potassium carbonate in refluxing methanol for 2 hrs. ... 

Substituted oxazoles through the reaction of p-tolylsulfonylmethyl isocyanide (TosMIC) with aldehydes in protic solvents at refluxing temperatures. 

Tosylmethylisocyanide (TosMIC) reacts with aldehydes via a [3+2] pathway, under basic conditions, to give 5-substituted oxazoles. In one example, the resulting oxazole product was used in the synthesis of a key intermediate for the hepatitis C drug candidate VX-497 (Scheme 56) <20020PD677>. K2CO3 is usually the base of choice for this reaction since stronger bases such as KO/-Bu lead to a cyanide product. 

The reaction of aryl aldehydes with benzotriazol-l-ylmethyl isocyanide (154), obtained in two steps from benzotriazole, formaldehyde and formamide, gives 5-aryl-substituted oxazoles in 35-69% yields (Scheme 71) <89TL6657>. 

About 30 years ago van Leusen and co-workers pioneered the condensation of TosMIC with aldehydes and ketones to prepare 4,5-disubstituted oxazolines that eliminate toluenesulfinic acid to yield 5-substituted oxazoles. This process continues today as an important method for constructing such analogues, as evidenced by the following examples. 

In related studies on the transformations of tosylmethyl isocyanide (24 TosMIC), van Leusen and co-workers found that the based-mediated condensation of 24 and a range of aldehydes yielded the corresponding 5-substituted oxazoles (c/, 28). This methodology thus provided an alternative to the Schollkopf reaction in the preparation of these compounds, and has subsequently become known as the van Leusen oxazole synthesis. 

Ganem and co-workers have developed the use of a Zn(OTf)2/TMSCl system to promote a variety of Passerini-type processes. The combination is active even for a,P-unsaturated aldehydes and usually problematic ketones. The promoter system was developed around a strategy of tethering nucleophilic functional groups to the isonitrile component to intercept the transient nitrilium species internally. Depending on the attached functionality either the a-hydroxy amide or a substituted oxazole could be obtained in high yield. For 1-isocyano-(2-morphilino)ethane (28), the reaction with... 

Oxazoles, Imidazoles, and Thiazoles. Resin-bound benzenesulfinic acid 52 obtained from sodium benzenesulfinate resin 43 (Scheme 12.13) could be treated with excess TEA and aldehyde in the presence of thiazohum catalyst to provide a-ketoamide in situ. Further reactions of the a-ketoamide with PPha/I, Lawesson s reagent, and EtOH/amine generated substituted oxazoles 56, imidazoles 57, and thiazoles 58 (Scheme 12.14). 

Carbonyl-substituted oxazoles 20 (aldehydes, ketones, carboxylic acids, and their derivatives) undergo a thermally induced rearrangement to the isomeric oxazoles 22, in which the residue located at the 4-carbonyl moiety and the 5-substitutent have changed places (CoRNFORTH rearrangement) [261] ... 

Among the oxazole syntheses not simply deducible from classical retrosynthesis approaches applying isocyanides as starting materials are of considerable interest [263]. (a) In the van Leusm synthesis, TosMIC reacts with aldehydes under base catalysis (e.g., K2CO3) to give 5-substituted oxazoles 41 ... 

The aldehyde functionality present in 3-phenyl-2H-azirine-2-carbox-aldehyde reacts selectively with amines and with Qrignard and Wittig reagents to give a variety of substituted azirines. These azirines have been used, in turn, to prepare a wide assortment of heterocyclic rings such as oxazoles, imidazoles, pyrazoles, pyrroles, and benzazepins. ... 

Monosubstituted and 4,5-disubstituted oxazoles were easily obtained from aryl-substituted tosylmethyl isocyanides and aldehydes . Tosyloxazoles 107, prepared from TosMIC 106 and carboxylic acid chlorides, led to 5-substituted derivatives 108 through ultrasound-promoted desulfonylation <00JCS(P1)527>. 

A systematic study of substitution reactions of oxazole itself has not been reported. Bromination of 2-methyl-4-phenyloxazole or 4-methyl-2-phenyloxazole with either bromine or NBS gave in each case the 5-bromo derivative, while 2-methyl-5-phenyloxazole was brominated at C(4). Mercuration of oxazoles with mercury(II) acetate in acetic acid likewise occurs at C(4) or C(5), depending on which position is unsubstituted 4,5-di-phenyloxazole yields the 2-acetoxymercurio derivative. These mercury compounds react with bromine or iodine to afford the corresponding halogenooxazoles in an electrophilic replacement reaction (81JHC885). Vilsmeier-Haack formylation of 5-methyl-2-phenyloxazole with the DMF-phosphoryl chloride complex yields the 4-aldehyde. 

The reaction of -halo carbonyl compounds with primary amides is appropriate for oxazoles containing one or more aryl groups . Ureas form 2-aminooxazoles. Formamide can be used resulting in a free 2-position in the oxazole. A convenient synthesis of 5-substituted-4-cyanooxazoles 223 is based on the condensation of -hydroxy—cyanoenamines 222 with trimethyl orthoformate (Scheme 109). The cyanoenamine intermediates 222 are derived from Lewis acid-catalyzed Passerini reactions between /-butyl isonitrile and aldehydes <2002S1969>. 

Various other [3 + 2] cycloadditions, affording chiral, anellated C6o derivatives with stereogenic centers in the addends are reported in literature. The products were generally obtained as racemates and resulted from reaction of buckminsterfullerene with species like 2,3-disubstituted 2//-azirincs (via nitrile ylides [under direct irradiation] or via 2-azaallenyl radical cations [sensitization by photoinduced electron transfer]),365 1-substituted 5-diazopentane-1,4-diones (via cyclic carbonyl ylides),366 7-alkylidene-2,3-diazabicyclo[2.2.1] hept-2-ene (via a diradicaloid trimethylenemethane derivative),367 1-benzylpy-razolidine-3-ones in the presence of aldehydes (via pyrazolidinium ylides),368 2-trifluoromethyl-2,5-dihydro-l,3-oxazol-5-ones (via nitrile ylides),369 nitro-alkanes in the presence of triethylamine and trimethylsilyl chloride (via N-silyloxynitrones),370 or dv-HOCH2 CH=C H C H 2 OCO 2 H( in the presence of... 

Even in the presence of nucleophiles like methanol, these sterically hindered enols only afforded benzofurans under oxidative conditions. Importantly, when stable enols of the Fuson type, which are less sterically hindered in the P-position, were oxidized with one-electron oxidants a-substituted carbonyl compounds 31 and 34 were obtained with water and various alcohols [64]. With acetonitrile, formation of the oxazole 32 was observed. A related example of this chemistry can be found in the context of Fuson s oxidation studies using Pb(OAc)4 [123] that provided the a-acetoxy aldehyde 31c from 30. To explain the products 31 and 34, three different mechanistic hypotheses were advanced (Scheme 3) [64] similar to the ones rationalizing the benzofuran formation. 

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