4.5- Disubstituted oxazoles, Schollkopf oxazole

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. 

The Schollkopf reaction has found considerable use in the preparation of eompounds containing 4,5-disubstituted oxazoles. 4,5-Disubstituted oxazole 30 served as a key intermediate in DuPont s synthesis of benzamidine 31, a Factor Xa inhibitor. The Sehdllkopf reaetion has similarly found use in the preparation of 4,5-disubstituted oxazoles for P3-adrenergie receptor agonist," Fe(II)-form-selective E. coli methionine aminopeptidase inhibitor," and prostacyclin receptor antagonist programs. The robustness of this synthetic methodology has also led to the use of the Schollkopf oxazole synthesis as a test reaction in the evaluation of a number of flow-reactor systems. ... 

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]. 

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