Oxidation and Reduction of Heterocyclic Rings

Generally speaking the electron-poor heterocycles are more resistant to oxidative degradation than are electron-rich systems - it is usually possible to oxidise alkyl side-chains attached to electron-poor heterocycles whilst leaving the ring intact this is not generally true of electron-rich, five-membered systems. 

The conversion of monocyclic heteroaromatic systems into reduced, or partially reduced derivatives is generally possible, especially in acidic solutions where it is a cation which is the actual species reduced. It follows that the six-membered types, which always have a basic nitrogen, are more easily reduced than the electron-rich, five-membered counterparts heteroaromatic quaternary salts are likewise easily reduced. 

The use of biological methods has a small but significant niche in synthetic heterocyclic chemistry, being used both on a research scale and for fine chemicals production. The processes may use isolated enzymes or whole microorganisms, the main reactions being oxidations of a heterocyclic nucleus or of side-chains. Some other reaction types are referred to later in the book, for example enzyme-catalysed base exchange in nucleosides and the deamination of adenosine. 

The oxidation of pyridines to pyridones and the selective oxidation of a side-chain in alkylpyridines and other azines, have been well studied. 

The enantioselective cis dihydroxylation of benzothiophenes and benzofurans by Pseudomonas putida is analogous to well known conversions of simple benzenoid compounds, but in the heterocyclic context, hydroxyl groups introduced at an a-carbon easily epimerise. Indole gives indoxyl probably via dehydration of an intermediate 2,3-diol. 

The ease with which an orf/to-qninodimethane can be formed is related to the stability of the aromatic heterocycle from which it is derived and to the degree of donble-bond character between the ortho ring carbons. The first of these aspects can be nicely illnstrated by comparing the thiophene 2,3-qninodimethane with its furan counterpart - the latter is more stable than the former - the thiophene-derived species has mnch more to lose in its formation from an aromatic thiophene (and much more to gain by reacting to regain that aromaticity) than does the latter. 

Three main strategies have been employed for the prodnction of heterocyclic orffto-quinodimethanes a 1,4-elimination, the chelotropic loss of snlfur dioxide from a 2,5-dihydrothiophene S. iS -dioxide and the electrocyclic ring opening of a cyclobnteno-heterocycle each of these is illustrated diagramatically below. 

The use of cyclobuteno-heterocycles is of course dependent on a convenient synthesis (for an example, see 14.13.2.5), but when available, they are excellent precursors, only rather moderate heating being required for ring opening, as shown by the example below, in which the initial Diels-Alder adduct is aro-matised by reaction with excess quinone.  

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