Acylation ethyl isocyanoacetate

Treatment of N-benzoyl-L-alanine with oxalyl chloride, followed by methanolic triethylamine, yields methyl 4-methyl-2-phenyloxazole-5-carboxylate 32 <95CC2335>. a-Keto imidoyl chlorides, obtained from acyl chlorides and ethyl isocyanoacetate, cyclise to 5-ethoxyoxazoles by the action of triethylamine (e.g.. Scheme 8) <96SC1149>. The azetidinone 33 is converted into the oxazole 34 when heated with sodium azide and titanium chloride in acetonitrile <95JHC1409>. Another unusual reaction is the cyclisation of compound 35 to the oxazole 36 on sequential treatment with trifluoroacetic anhydride and methanol <95JFC(75)221>. 

Regiochemical synthesis of 1-substituted imidazole-4-carboxylates can be achieved by treatment of a (Z)-)3-dimethylamino-of-isocyanoacrylate with an alkyl or acyl halide (see Section 2.1.1 and Scheme 2.1.8), by cyclization of 3-alkylamino-2-aminopropanoic acids with triethyl orthoformate followed by dehydrogenation of the initially formed imidazoline (see Section 3.1.1 and Scheme 3.1.2), by condensation of 3-arylamino-2-nitro-2-enones with ortho esters in the presence of reducing agents (see Section 3.1.1 and Scheme 3.1.4), by reaction of an alkyl A -cyanoalkylimidate with a primary amine (see Section 3.2 and Scheme 3.2.1), the poor-yielding acid-catalysed cyclization of a 2-azabutadiene with a primary amine (see Section 3.2 and Scheme 3.2.3), the cyclocondensation of an isothiourea with the enolate form of ethyl isocyanoacetate (see Section 4.2 and Scheme 4.2.5), and from the interaction of of-aminonitrile, primary tunine and triethyl orthoformate (see Chapter 5, Scheme 5.1.5, and Tables 5.1.1 and 5.1.2). 

In two modern versions of ring closures in this category of ring synthesis, oxazoles are produced by base-catalysed closure of iniino-chloride derivatives of glycine, obtained by acylation of ethyl isocyanoacetate and in the second, by base-catalysed closure of 3-acylamino-2-iodo-l-phenylsulfonylalkenes. In yet another use of an isonitrile, 2-tosylaminoimidazoles can be prepared. ... 

Yuan and co-workers reported a general synthesis of 2-acyl-5-aIkoxyoxazoles via cyclization of a-ketoimidoyl chlorides (Scheme 1.97). Acylation of ethyl isocyanoacetate with an acid chloride yielded an a-ketoimidoyl chloride 359, which was not isolated but cyclized upon addition of triethylamine to afford a 2-acyl-5-alkoxyoxazole 360. 

In 1980, Kozikowski reported that the combination of a selenol ester cf., 12) and copper(I) oxide also functioned as a suitable acylating agent in the Schdllkopf reaction. For example, ethyl isocyanoacetate (8) and selenol ester 12 were condensed in the presence of excess CU2O and triethylamine to provide oxazole 13 in 85% yield after 12 h at ambient temperature. This methodology subsequently found use in Weinreb s approach to amphimedine. ... 

The mechanism of the condensation in Part D probably involves thioformylation of the metallated isocyanoacetate followed by intramolecular 1,1-addition of the tautomeric enethiol to the isonitrile. This thi2izole synthesis is analogous to the formation of oxazoles from acylation of metallated isonitriles with acid chlorides or anhydrides. " Interestingly, ethyl formate does not react with isocyanoacetate under the conditions of this procedure. Ethyl and methyl isocyanoacetate have been prepared in a similar manner by dehydration of the corresponding N-formylglycine esters with phosgene and trichloromethyl chloroformate, respectively. The phosphoryl chloride method described here was provided to the submitters by Professor U. Schollkopf and is based on the procedure of Bohme and Fuchs. The preparation of O-ethyl thioformate in Part C was developed from a report by Ohno, Koi/.uma, and Tsuchihaski. " ... 

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