Isonitrile synthesis, oxazole

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. ... 

Addition to Aldehydes. The Vedejs oxazole metalation has often been applied in the addition of oxazoles to aldehydes. In order to avoid ring opening to the isonitrile, the oxazole is first complexed with borane, then reacted with BuLi to generate the 2-metalo nucleophile (eq 15). This has been applied in the synthesis of a-ketooxazole inhibitors, and angiotensin II (AT2)... 

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. " ... 

The reaction of -halo carbonyl compounds with primary amides is appropriate for oxazoles containing one or more aryl groups . Ureas form 2-aminooxazoles. Formamide can be used resulting in a free 2-position in the oxazole. A convenient synthesis of 5-substituted-4-cyanooxazoles 223 is based on the condensation of -hydroxy—cyanoenamines 222 with trimethyl orthoformate (Scheme 109). The cyanoenamine intermediates 222 are derived from Lewis acid-catalyzed Passerini reactions between /-butyl isonitrile and aldehydes <2002S1969>. 

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>. 

On the basis of the same principle, we developed a three-component synthesis of macrocycles starting from azido amide (46), aldehyde (47) and a-isocyanoaceta-mide (48) (the cx-isocyanoacetamides are easily available, see [84—86]) bearing a terminal triple bond (Scheme 11) [87]. The sequence is initiated by a nucleophilic addition of isonitrile carbon to the in situ generated imine 50 led to the nitrilium intermediate 51, which was in turn trapped by the amide oxygen to afford oxazole 52 (selected examples [88-94]). The oxazole 52, although isolable, was in situ converted to macrocycle 51 by an intramolecular [3+2] cycloaddition upon addition of Cul and diisopropylethylamine (DIPEA). In this MCR, the azido and alkyne functions were not directly involved in the three-component construction of oxazole, but reacted intramolecularly leading to macrocycle once the oxazole (52) was built up. The reaction created five chemical bonds with concurrent formation of one macrocycle, one oxazole and one triazole (Scheme 15). 

As illustrations of the variety of methods available, the three processes below show (i) the addition of isonitrile anions to a,P-unsaturated nitro-compounds, with loss of nitrous acid to bring about aromatisation, (ii) the interaction of thioglycolates with 1,3-dicarbonyl-compounds, for the synthesis of thiophene 2-esters, and (iii) the cycloaddition/cycloreversion preparation of furans from oxazoles. 

Several new synthetic routes for the synthesis of highly substituted oxa-zoles were proposed. For instance, oxazoles 106 resulted from an unexpected reactivity of isonitriles 104 toward carboxylic acids 105 in the presence of ZnRro (13AGE10878). The reaction was proposed to proceed around the coordination sphere of a ZnBr2-isonitrile complex and involves three units of... 

Potassium carbonate Synthesis of heterocyclics with 1-sulfonyl-l-isonitriles Oxazoles from 0x0 compds. 

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