Schollkopf oxazole synthesis

This reaction was first reported by Schollkopf and Schroder in 1971 It is the formation of a 2-unsubstituted oxazole derivative by the condensation of an a-metalated isocyanide with an acylating reagent. Therefore, this reaction is known as the Schollkopf oxazole synthesis or Schollkopf reaction. ... 

Other references related to the Schollkopf oxazole synthesis are cited in the literature. 

Schollkopf Oxazole Synthesis Brian A. Lanman and Xiaojun Han 4.5.1 Description... 

The Schollkopf oxazole synthesis, also known as the Schollkopf reaction, is the base-promoted condensation of an alkyl isocyanide (1) and an acylating agent (2) to produce an oxazole substituted at either (or both) the 4- or 5-position (3). 

One drawback of the use of weak bases as in situ promoters for the Schollkopf oxazole synthesis is the long time typieally required to drive such reactions to completion. For example, the condensation of methyl isocyanoacetate (14) and 3,4,5-trimethoxybenzoyl chloride (19) in the presence of DBU provides only an 8% yield of oxazole 21 after 2 h at ambient temperature. This limitation can be overcome by employing Verkade s prophosphatrane superbase (20), which, in the case of the reaction of 14 and 19, results in near-quantitative formation... 

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. ... 

Ohba and co-workers have demonstrated that A -protected a-amino esters are compatible with the Schollkopf oxazole synthesis cf., 38->39). In the case of ammo esters derived from natural amino acids (e.g., 38), the presence of an additional acidic N-H bond in the AABoc ester substrate necessitated the use of an added excess of metalated isocyanide (2.5 equiv was found to be optimal) to obtain maximal yields. Under optimized conditions, oxazoles (39) were obtained in good yield from iV-Boc glycine, alanine, and phenylalanine. Oxazole formation from iV-Boc serine (which possesses an additional acidic site in its hydroxylic side chain) proceeded in good yield (66%) using 3.5 equiv lithiated methyl isocyanide. Notably, no epimerization was detected in the reaction of N-Boc alanine methyl ester with lithiated methyl or ethyl isocyanide under these conditions. Minor epimerization was observed (91-92% ee product) with substrates that lacked a carbamate NH hydrogen e.g., A -Boc proline methyl ester), however. ... 

Lactones have also been found to be competent substrates for the Schollkopf oxazole synthesis. For example, treatment of aldonic acid lactone 40 with ethyl a-isocyanoacetate (8) and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) at ambient temperature provided acyclie sugar oxazole 41 in 49% yield. ... 

R] Wang, Z. Schollkopf Oxazole Synthesis, in Comprehensive Organic Name Reactions and Reagents, vol. 3 Wiley Hoboken, NJ, 2009 pp 2529-2532. 

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