Quinone methides, generation phenols, oxidation

Several general synthetic methods have been developed that utilize the novel reactivity of quinone methides generated by oxidation of phenol precursors. Angle and Ranier have generated 2,6-dialkyl or 2,6-dialkoxy-substituted / -quinone methides 51 by oxidation of the corresponding phenols with Ag20. 

Another interesting example of ort/zo-addition to phenol complexes is its reaction with aldehydes. In the presence of a weak base, the aldehyde undergoes an aldol condensation at C2 to give a rare example of a stable o-quinone methide complex. In Fig. 9 citronellal (34) is combined with phenol complex 20 to generate the quinone methide 35. Upon oxidative decomplexation a hetero-Diels-Al-der reaction occurs to form the benzochromene core 37 in 52% yield [48]. 

Cyclization of quinone methides.2 p-Quinone methides, particularly those substituted at the 2- and 6-positions, are stable enough to be characterized by IR and NMR, and can be generated in fairly high yield by oxidation of a phenol with Ag,0 (10 equiv.) in CH2C12. When substituted by a suitable terminator, these quinonemethides can undergo Lewis-acid-catalyzed cyclization. Suitable terminators that can survive the initial oxidation include allylsilanes and 3-keto esters. In the latter case, the initial product undergoes oxidation to afford a cyclohexenone. 

The various methods of generating o-quinone methides,4-5 including the thermal or (Lewis) acid-catalyzed elimination of a phenol Mannich base,149 150-160-161163 the thermal or (Lewis) acid-catalyzed dehydration of an o-hydroxybenzyl alcohol (ether),147-149-151-153-156-157-162-163-165-168 171-175-178-183 the thermal 1,5-hydride shift of an o-hydroxy styrene,171-173 175 178-183 the thermal dissociation of the corresponding spirochromane dimer,158 163-164,166 oxidation of substituted o-alkylphenols,152-170 and the thermal or photochemical-promoted cheletropic extrusion154-155 159 of carbon monoxide, carbon dioxide, or sulfur dioxide (Scheme 7-III), as well as their subsequent in situ participation in regiospecific, intermolecular [4 + 2] cycloadditions with simple olefins and acetylenes,147 149-151 152 153159 162-164... 

The structural design of 68 seems to be the key to the problem. In fact, an electrochemical study has shown that the biological effect seems triggered by the reversible oxidation of the ferrocene entity, which could then be followed by a premature transformation of the phenol via generation of an intermediate carbenium ion, leading to a fairly stable quinone methide 70 [94], It is well documented that electrophilic species such as quinone methides have the potential to alkylate cellular macromolecules to produce a cytotoxic effect [151-153]. Complex 69, however, which is isolated in the form of the stable trans isomer, cannot produce a stabilized quinone methide. It is thus clear that for targeted organometaUic products such as 68 and 69, structural considerations come to the fore. 

The stabilizing activity of phenols is based on scavenging of the alkyl-peroxy radicals (POO ) generated in oxidizing polymers. Participation of POO in the oxidation chain transfer is thus reduced. Reactivity of phenolics with POO results, however, in chemical transformation of the original phenolic structure (antioxidant consumption). Hence, the protection of the polymer matrix is diminished in stepwise fashion. Crossconjugated dienoide compounds, e.g. quinone methides, account... 

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