Oxazoles from TOSMIC

Van Leusen and co-workers also demonstrated the utility of dilithio-tosylmethyl isocyanide (dilithio-TosMIC) to extend the scope of the application. Dilithio-TosMIC is readily formed from TosMIC and two equivalents of n-butyllithium (BuLi) in THF at -70"C. Dilithio-TosMIC converts ethyl benzoate to oxazole 14 in 70% yield whereas TosMIC monoanion does not react. In addition, unsaturated, conjugated esters (15) react with dilithio-TosMIC exclusively through the ester carbonyl to provide oxazoles (16). On the other hand, use of the softer TosMIC-monoanion provides pyrroles through reaction of the carbon-carbon double bond in the Michael acceptor. 

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>. 

Recently, Addie and Taylor extended the synthetic utility of TosMIC by developing conditions to effect desulfonylation of a 5-substituted 4-tosyloxazole 405 (Scheme 1.109, p. 90). Their plan was to generate the dianion of 5-methyl-4-tosyloxazole 402 followed by quenching with an electrophile to produce a 5-substituted-4-tosyloxazole 404. Desulfonylation of 404 would provide a novel entry to 5-substituted oxazoles 405, thereby avoiding the use of toxic methyl isocyanide. In addition, desulfonylation of the 5-substituted 4-tosyloxazoles 406 normally obtained from reaction of TosMIC with an ester, acid chloride, or acid anhydride would further broaden the scope and use of this reaction. 

Further refinements from these workers led to a general synthesis of 5-aryl(heteroaryl)oxazoles 411 from aromatic and heterocyclic aldehydes using TosMIC and a resin-bound quaternary ammonium hydroxide. This approach greatly simplifies purification. The base and toluenesulfinic acid are removed by simple filtration to afford 411 in quite acceptable purity for biological screening. 

Henaff and Whiting prepared the 5-(3-tri-n-butylstannylallyl)oxazole 1624 from 3-butyn-l-ol and TosMIC (Scheme 1.415). This was a key intermediate in their synthetic approach to phthaloxazolin A 1177 (R = H). 

Bristol-Myers Squibb chemists converted substituted 4-nitrobenzaldehydes to 5-(substituted 4-nitrophenyl)oxazoles 1625 using TosMIC (Scheme 1.416). As an example, 5-(2-methoxy 4-nitrophenyl)oxazole 1625 (R = CH3O), evaluated as an IMPDH antagonist, was prepared from 2-methoxy-4-nitrobenzaldehyde in 84% yield. 

Reactions of aromatic or heteroaromatic aldehydes 144 with a ROMPgel Tosmic reagent 143, available from the ring opening metathesis of 142, allowed the preparation of a small library of oxazoles 145 in high yields and with minimal purification <01OL271>. 

Polymer-supported TosMIC reagent 1612 has been described and employed in an oxazole synthesis involving minimal purification [1203]. ROMPgel TosMIC reagent 1612 was prepared from the corresponding polymeric formamide 1611 by dehydration with phosphoryl chloride in 100% yield. 1611 was obtained by ROM polymerization of 1610 in 100% yield [1203]. 

Many 5-aryl-l,3-oxazoles, bearing various functions at the aryl group, can be prepared in good yields of 68-90% and with high purities from aldehydes and ROMPgel TosMIC reagent 1612 they are purified only by filtration without any need for chromatography [1203]. This makes the method particularly well-suited for use in combinatorial chemistry. 

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 ... 

Oxazoles are a common structural motif foxmd in numerous molecules that display antiviral, antifungal, antibacterial, and antiproliferative activities [150,151]. Classical methods for oxazole synthesis include Robinson-Gabriel synthesis by dehydration of 2-acylaminokefones, Fischer oxazole synthesis from cyanohydrins and aldehydes, Bre-dereck reaction with a-haloketones and formamide. Van Leusen reaction with aldehydes and TosMIC, Hantzsch reaction, and aza-Wittig reaction [152]. 

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