Isocyanides 5- -2,4-disubstituted oxazoles

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>. 

For arylsulfonyl methyl isocyanides (3), [3 + 2] cycloadditions with aldehydes yielding 4,5-disubstituted oxazoles (N) have been reported [115]. The cycloaddition takes place in the same manner as with the use of isocyano esters (A, = H) ... 

The tosyl compound reacts with aldehydes in the presence of potassium carbonate to yield 5-alkyl- or 5-aryl-oxazoles, the intermediate dihydrooxazoles (which can be isolated) eliminating toluene-p-sulfinic acid (Scheme 30). Use of acyl chlorides in place of aldehydes leads to 4-tosyloxazoles (288). Furthermore, alkylation of tosylmethyl isocyanide with an alkyl halide RfX, followed by treatment with an aldehyde R2CHO, yields a 4,5-disubstituted oxazole (289). A related reaction is that of A-tosylmethyl-iV -tritylcarbodiimide with aromatic aldehydes under phase-transfer catalysis to yield 2-tritylaminooxazoles which are readily converted into 2-amino-5-aryloxazoles (equation 117) (81JOC2069). 

Chiral isocyanides such as 198 have also been used for the synthesis of chiral 4,5-disubstituted oxazoles such as 199, which are potentially useful in fluorescence-detected circular dichroism for on-column capillary electrophoresis (Equation 12) <1996JOC8750>. 

In the Schollkopf synthesis, a-metalated isocyanides 13 (from isocyanides and /z-butyllithium) react with acid chlorides to give 4,5-disubstituted oxazoles 14 via C-acylation and electrophilic C-O bond formation. 

Schollkopf and Gerhart " pioneered the use of metallated isocyanides in organic synthesis. This section discusses the versatility of such intermediates for preparing monosubstituted and disubstituted oxazoles as well as the parent 1, itself. In addition, continuing advances in solid-phase synthesis have enhanced the use of tosylmethyl isocyanide (TosMIC) for oxazole synthesis several examples are presented. 

Ulrich Schollkopf (1927-1998) and Rolf Schroder of the University of Gottingen first reported the preparation of 4,5-disubstituted oxazoles (3) from the condensation of a-metalated alkyl isocyanides and a range of acid chlorides, esters, and amides in 1971. 

Notably, when arylmethylisocyanides are reacted with acid chlorides in the presence of 2,6-lutidine as a base, 2,5-disubstituted oxazoles are formed instead of the 4,5-disubstituted oxazoles obtained when using SchOllkopf conditions (nBuLi). This effect is believed to be due to primary acylation of the isocyanide functionality [265]. 

Isocyanides are very usefiil tools in the synthesis of N-heterocycles such as indoles, imidazoles, tetrazoles, and oxazoles. To form 2,3-disubstituted indoles such as 3-substituted 2-iodo indoles 1518, o-isocyano cinnamates 1517 are important intermediates. They are prepared in high yield (87% for 1517) by dehydration of o-(N-formylarnino)cinnamate 1516 with phosgene [1153, 1166]. 

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