Leusen oxazole Synthesis

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

Brooks, D. A. van Leusen Oxazple Synthesis in Name Reactions in Heterocyclic Chemistry, Li, J. J. Corey, E. J., Eds. Wiley Sons Hoboken, NJ, 2005, 254—259. (Review). 

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.  

In 1972, van Leusen, Hoogenboom and Siderius introduced the utility of TosMIC for the synthesis of azoles (pyrroles, oxazoles, imidazoles, thiazoles, etc.) by delivering a C-N-C fragment to polarized double bonds. In addition to the synthesis of 5-phenyloxazole, they also described reaction of TosMIC with /7-nitro- and /7-chloro-benzaldehyde (3) to provide analogous oxazoles 4 in 91% and 57% yield, respectively. Reaction of TosMIC with acid chlorides, anhydrides, or esters leads to oxazoles in which the tosyl group is retained. For example, reaction of acetic anhydride and TosMIC furnish oxazole 5 in 73% yield.  

Van Leusen and co-workers also demonstrated the condensation of heteroaromatic aldehydes with TosMIC. Table 6.7.1 shows the 5-heteroaryloxazoles 6 prepared in 47-88% yield in the presence of equimolar amounts of potassium carbonate in refluxing methanol. 

Van Leusen and Possel described the use of mono-substituted tosylmethyl isocyanides (TosCHRN=C R = alkyl, benzyl, allyl) in the synthesis of 4,5-substituted oxazoles. For example, 4-ethyl-5-phenyloxazole (8) was prepared in 82% yield by refluxing a-tosylpropyl isocyanide (7) and benzaldehyde for 1 hr with 1.5 equivalent of K2CO3 in MeOH. 

The propensity of isocyanides to undergo nucleophilic a-additions at the terminal carbon, together with the presence of an activated methylene and a potential leaving group (i.e. tosyl), led van Leusen to suggest the following reaction path  

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 259, Springer-Verlag Berlin Heidelberg 2009 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 278, Springer International Publishing Switzerland 2014 

van Leusen, A. M. van Leusen, D. In Encyclopedia of Reagents of Organic Synthesis, Paquette, L. A., Ed. Wiley New York, 1995 Vol. 7, A9T3—A9T9. (Review). 

---

T10425>. Through a proper use of the Suzuki-Miyamura and van Leusen oxazole synthesis it was possible to synthesize a wide variety of aromatic derivatives substituted with oxazole rings. The strategy was based on the initial synthesis of the aromatic scaffold and the subsequent reaction of the carbonyl functions with toluenesulfonylmethyl isocyanide (TosMIC) as depicted in the following scheme<07S3653>. 

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. 

In analogy to the van Leusen oxazole. synthesis (cf. p. 173), the anion of TosMIC adds to the imine function and the addition product 46 cyclizes to the imidazoline 47, which undergoes base-induced elimination of sulfinic acid producing the imidazole 45. 

---