5-unsubstituted oxazoles

This method is not suited to the preparation of 2-unsubstituted oxazoles the main difficulty is the preparation of the acyloin formates themselves. Bredereck and Gompper94 introduced a new method of synthesizing the acyloin formates (54) by the treatment of acyloins in formic acid solution in the cold with either phosphorus trichloride or thionyl chloride. The yields in the three reported cases are 61-91%. These a-formyloxy ketones on boiling with formamide in formic acid afford the corresponding oxazoles. unsubstituted in the 2-position, in 61-75% yields.94... 

In a variation94 of this procedure, acyloins themselves have been converted directly into 2-unsubstituted oxazoles by reaction with formamide and concentrated sulfuric acid at 100°-150o. The yields in this case, compared to overall yields of the two stages of the previous method, are either nearly the same or better. 

Metalation of 2-unsubstituted oxazoles with n-butyllithium at low temperature produces the corresponding 2-lithio derivatives, which are useful intermediates for the preparation of deuterium-labeled com-... 

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. ... 

Scheme 10 Synthesis of a 5-Unsubstituted Oxazole-Based Peptide from Hydroxymethylene Amides via Bro-modihydrooxazolesl65-67 ...

The synthesis of 2-acyloxazoles has always been a challenging task. Their synthesis through the use of metallated oxazole is troubled by its ring opened form (as an enolate isonitrile) which is predominant. A very useful new procedure for this synthetic approach is offered by the use of i-PrMgCl as a metallating reagent and a Weinreb amide 102 as the electrophile. This procedure was applied both to 5-(hetero)-aryl substituted oxazoles and unsubstituted oxazoles <07JOC5828>. 

The particular reaction described in Scheme 2 using dimethyl diazomalonate produces oxazoles 5 that bear a methoxy group at C-5. If desired, this substituent may be removed in some cases by reductive cleavage using LiB(Et)3H to give the 5-unsubstituted oxazoles 6.3.15 Alternatively, the 5-unsubstituted derivatives 6 may be obtained directly through the use of diazo formylacetate (2) in place of dimethyl diazomalonate (1).3 15 Some additional, representative examples of the use of 1 and 2 are shown below in the Table. 

In a recent work, Piguel has shown that direct alkenylation of various electron-rich heterocycles by alkenyl bromides is possible under copper catalysis [99], Employing a combination of Cul with tra n v-1,2-A, /V - dim e l It y Ic y c I o It exan e diamine ligand and fBuOLi base, 5-aryloxazoles, benzothiazole, benzoxazole, and unsubstituted oxazole were alkenylated by P-bromostyrenes and isocrotyl bromide in good... 

Amino acid-derived aldehydes can be converted into 5-unsubstituted oxazoles and in a related sense, imidazoles can be produced by introducing ammonia to an 2-acylamino-ketone. ... 

Advantages of this methodology are mild reaction conditions that tolerate a variety of sensitive functional groups and little observed epimerization with optically active side chains. It is also noteworthy that 5-unsubstituted oxazoles are available, which complements the Dess-Martin periodinane-l2/(C6H5)3P proto-... 

The only review of this subject continues to be Traldi and co-workers. °° The majority of oxazoles follow the main ring-cleavage fragmentation pattern of unsubstituted oxazole radical cation formation, cleavage of the O-C2 bond, and loss of CO, followed by loss of HCN or nitrile (Fig. 2.15). In the case of oxazole itself, an initial loss of HCN is believed to lead to oxirene radical cation. ... 

As detailed previously, Vedejs showed that trapping of 2-lithiooxazole with 1,2-diiodoethane yields 2-iodooxazole. Daugulis has demonstrated non-cryogenic conditions for the direct bromination of C2-unsubstituted oxazoles using dibromotetrafluoroethane as the electrophile. The Sandmeyer reaction can be utilized to prepare 2-chlorooxazoles from 2-aminooxazoles. Hexachloroethane can also be used as an electrophile for the direct chlorination of 2-lithiooxazole. The conversion of 2-oxazolones to 2-trifloyloxazoles is also possible however, 2-trifloyloxazoles decompose at high temperatures. ... 

To prepare 4-iodooxazoles, Vedejs protocol with DMPU cosolvent allows for efficient synthesis. When DMF is used as the solvent, 2,4-unsubstituted oxazoles can be regioselectively brominated at the 4-position widi NBS on kilogram scale. Hunsdiecker reaction of a C4-carboxylic acid also provides the C4 bromide. With a substituted C2 position, Nicolaou and co-workers achieved chlorination of the C4 position using NCS to prepare an intermediate in the partial synthesis of diazonamide Similar to C2 trifloyloxazole synthesis, trapping of 4-oxazolones with triflic anhydride yields 4-trifloyloxazoles. These triflates, in contrast to 2- or 5-trifloyloxazoles are stable and can generally be utilized in cross-coupling reactions. 

Among the five-membered heterocycles containing two heteroatoms, oxazole derivatives and imidazole derivatives have been reported to react. Matsuo and Miki have shown that the bicyclic adduct 168 from oxazole derivative 167 can be isolated as endo and exo isomers. With unsubstituted oxazole the adduct undergoes further reaction. 

The unsubstituted pyrrolo[l,2-f]oxazol-3-one 295 underwent a dihydroxylation with catalytic osmium tetroxide to exclusively give diol 296. This diol resulted from attack of the oxidizing agent from the concave face of the molecule due to the pseudoaxial protons that sterically hinder the /3-face to be attacked by the osmium reagent (Equation 51) <2004AJC669>. 

By analogy with oxazoles and N-substituted imidazoles, thiazoles and benzothiazoles unsubstituted at C-2 undergo direct metalation at that position, with sodium, lithium, or magnesium reagents (Scheme 91)[79MI1 ... 

Isocyanides are useful reagents for the preparation of oxazoles unsubstituted at C-2. For example, TosMIC was used to generate the oxazole ring in a synthesis of phthoxazolin A 37 <990L1137>. However in the reaction of IV-tosyl aldimines with the isocyanide 38 the oxazoles that were isolated were 2 1 adducts 39 that had been further substituted at C-2 <98T12445>. 

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