Concluding Remarks

Squaric acid is in principle a pseudoaromatic and therefore stable four-membered compound designated as 3,4-dihydroxy-3-cyclobutene-1,2-dione. Characteristic square planarity brings it high acidity, a peculiar network, and a donor-acceptor triad. Nevertheless, its intrinsically strained and highly oxygenated character makes it extraordinarily useful in synthesis. Once the cyclobutenedione skeleton is converted into the hydroxycyclobutenone skeleton, it can undergo further ring transformation either by thermal concerted rearrangements (chiefly depending on electrocyclic ring opening and ring closure) or by reactions induced by a reactive intermediate (including cation, radical, and divalent species). The directed synthesis of various heterocy-cles is accomplished by virtue of incorporation of heteroatom(s) on one or more of four possible sites of the four-membered ring and execution of the above ring transformation. Fortunately, the methods developed for introduction of substituents range from nucleophilic to electrophilic conditions and from ionic to radical and organometallic coupling reactions. It is evident from the cumulative successes shown in this review article that squaric acid plays the role of a useful synthetic C-4 building block for construction of biologically interesting oxygen, nitrogen, and sulfur heterocycles, if combined appropriately with corresponding heteroatoms. Bioactive hetero-cycles can also be provided by derivatization of the cyclobutenedione ring as retained. This utilization comes from the bioisostere concept and from its versatility as a linker of bioconjugates. In these cases, a squaramide form is often employed in the acid interconversion. Conclusively, the small molecule of squaric acid is able to produce a big effect on the synthesis of biologically interesting heterocycles.

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