Furan derivatives tetrasubstituted

R. Bossio and co-workers developed a novel method for the synthesis of tetrasubstituted furan derivatives. The Passerini reaction between arylglyoxals, isocyanides, and cyanoacetic acids led to the formation of A/-substituted 3-aryl-2-cyanoacetoxy-3-oxopropionamides, which in the presence of amine bases underwent a Knoevenagei condensation providing A/-substituted 3-aryl-cyano-2,5-dihydro-5-oxofuran-2-carboxamides. 

Several tetrasubstituted furan derivatives have been prepared by the Feist-Benary reaction. For example, Stetter and Lauterbach demonstrated that 1,3-cyclohexanedione could serve as a P-dicarbonyl in combination with ethyl 2-chloroacetoacetate in the presence of potassium hydroxide to yield the corresponding fused tetrasubstituted furan derivative in good yield. ... 

The only tetrasubstituted furans that have been prepared using the Feist-Benary reaction are substituted tetrahydrobenzofurans and octahydrodibenzofurans. This strategy was pioneered by Stetter and Chatterjea and applied in a series of total syntheses by Magnus. Stetter demonstrated that 1,3-cyclohexanedione (30) can act as the P-dicarbonyl component and readily combines with either 3-bromo-2-ketobutyric (29) acid or ethyl 2-chloroacetoacetate (32) in the presence of potassium hydroxide to yield tetrahydrobenzofuran derivatives 31 and 33, respectively. ... 

The usefulness of allene derivatives has also been revealed in other examples. Thus, the annulated tetrasubstituted furan illustrated in the following scheme was delivered in a moderate yield using the diazoallene as precursor by a two-step reaction in the presence of Rh-catalyst <06S3605>. 

As can be seen, the reaction between the anisyl derivative and the acetoacetate provided also tetrasubstituted furans. A subsequent demethylation cyclization delivered furo[3,4-c]coumarins in a moderate yield <06JHC 1699>. 

Another three-component reaction between aldehydes, dimethyl acetylenedicarboxylate and cyclohexyl isocyanide in ionic liquid under mild conditions afforded tetrasubstituted furans in high yields as illustrated below <04S2376>. A similar reaction using 2-furyl-2-oxoacetamide derivatives instead of aldehydes produced substituted furylfurans <04TL7099>. 

Li P, Chai Z, Zhao G, Zhu S-Z (2008) Synthesis of 3-fluoro-2,5-disubstituted furans and further derivative reactions to access fluorine-containing 3,3 -bifurans and tetrasubstituted furans. Synlett 2547-2551... 

An indole 9 and antipyrine (11) were fluorinated to give the respective fluoro derivatives 10 and 12. Attempts to fluorinate furan, pyrrole, N-benzylpyrrole, ethyl 2-thienylacetate, and methyl 2-thiophenecarboxylate with various salts were all unsuccessful owing to excessive tar formation (90JA8563). Porphyrins are efficiently fluorinated at meso positions, and tetrasubstituted derivatives, such as meso-tetraphenylporphyrin, are inert. The preparation of a mixture of fluorinated derivatives 14-18 from 13 and monofluorination of 19 to give 20 are instructive. Interestingly, the products 14-18 were separated into pure components by simple silica gel chromatography (92TL1069). 

Multiple substitution of reactive aromatic compounds may occur. Thiophene gives a 2, 5-disubstituted and furan a 2,3,4, 5-tetrasubstituted derivative with mercury (II) acetate in boiling ethanol. The preferential mercuration of thiophene has been used for its removal from commercial benzene. Mercuration of ferrocene (p. 284) also occurs readily. 

---