Quinone methide nucleophile addition

This addition is general, extending to nitrogen, oxygen, carbon, and sulfur nucleophiles. This reactivity of the quinone methide (23) is appHed in the synthesis of a variety of stabili2ers for plastics. The presence of two tert-huty groups ortho to the hydroxyl group, is the stmctural feature responsible for the antioxidant activity that these molecules exhibit (see Antioxidants). 

Given their extraordinary reactivity, one might assume that o-QMs offer plentiful applications as electrophiles in synthetic chemistry. However, unlike their more stable /tora-quinone methide (p-QM) cousin, the potential of o-QMs remains largely untapped. The reason resides with the propensity of these species to participate in undesired addition of the closest available nucleophile, which can be solvent or the o-QM itself. Methods for o-QM generation have therefore required a combination of low concentrations and high temperatures to mitigate and reverse undesired pathways and enable the redistribution into thermodynamically preferred and desired products. Hence, the principal uses for o-QMs have been as electrophilic heterodienes either in intramolecular cycloaddition reactions with nucleophilic alkenes under thermodynamic control or in intermolecular reactions under thermodynamic control where a large excess of a reactive nucleophile thwarts unwanted side reactions by its sheer vast presence. 

The generated quinone methide intermediates, during the disassembly, are highly reactive electrophiles and rapidly react with any available nucleophile (methanol or tetrabutylammonium hydroxide under organic solvent conditions). We could not isolate any significant amount of material that derived from the core molecule, probably due to generation of a mixture of compounds by the addition of different nucleophiles to the quinone methide. This molecule acts as an amplifier of a cleavage... 

TABLE 9.2 Substituents Affect the Susceptibility of Quinone Methides to Nucleophilic Addition... 

Angle, S. R. Yang, W. Nucleophilic addition of 2 -deoxynucleosides to the o-quinone methides lO-(acetyloxy) and 10-methoxy-3,4-dihydro-9(2T/)-anthracenone. J. Org. Chem. 1992, 57, 1092-1097. 

Combination of an Ri, radical with an Ra radical yields the single p-qninone methide dimer (V). Here the quinone methide cannot become stabilized by an intramolecnlar addition reaction. Instead, nucleophilic attack of its y-carbon atom occurs by a hydroxyl ion from the medium, for example aromatization and protonation of the phenoxido ion thus formed give rise to guaiacylglycerol- 3-coniferyl ether (VI), again in racemic form dc-spite its two asymmetric carbon atoms. Since attack by the extraneous hydroxyl ion can occur on either side of C-y of the p-quinone methide (V), complete equilibration of the specific hydrogens from the original conifcryl alcohol moiety in the lower half of (V) presumably occurs (sec formulae on p. 131). 

The linker (49) is attached as an amide to the solid phase. Cleavage of the acyl group by a lipase generated a phenolate (50), which fragments to give a quinone methide (51) and releases the product (52). The quinone methide remains on the solid phase and is trapped by water or an additional nucleophile. 

Detection and characterization of a kinetic product of deoxyadenosine (dA) alkylation helps to reconcile the apparent contradiction between the strength of nucleophiles in DNA and their propensity for addition to a model quinone methide. (Adapted from Veldhuyzen et al., 2001)... 

However, this level of uniformity is not expected of all nucleophiles and substrates. An extreme example of variation in ApAR is provided by comparison of chloride and dimethyl sulfide as nucleophiles reacting, respectively, with the p-methoxybenzyl cation and the structurally very different electrophile, the di-trifluoromethyl quinone methide 57.220 In the case of the p-methoxybenzyl cation the addition of Me2S is more favorable than addition of chloride ion by a factor of 107-fold for the quinone methide it is 100 times less favorable. Toteva and Richard attribute the difference to the large and unfavorable steric and polar interactions between the positively charged... 

Nucleophilic addition of a-halo-4-tolylsulfonyl methyl anions to quinone methides has been reported to afford three kinds of products as a result of domino reactions. Two of them were identified as rearrangement products and one as the vicarious nucleophilic substitution (VNS) product. An unexpected 1,2-migration of the tosyl group was observed.180... 

Structure-reactivity studies on nucleophile addition to quinone methides 68... 

The neutral 1,4- and 1,2-quinone methides react as Michael acceptors. However, the reactivity of these quinone methides is substantially different from that of simple Michael acceptors. The 1,6-addition of protonated nucleophiles NuH to simple Michael acceptors results in a small decrease in the stabilization of product by the two conjugated 7T-orbitals, compared to the more extended three conjugated 7T-orbitals of reactant. However, the favorable ketonization of the initial enol product (Scheme 1) confers a substantial thermodynamic driving force to nucleophile addition. By comparison, the 1,6-addition of NuH to a 1,4-quinone methide results in a large increase in the -stabilization energy due to the formation of a fully aromatic ring (Scheme 2A). This aromatic stabilization is present to a smaller extent at the reactant quinone methide, where it is represented as the contributing zwitterionic valence bond structure for the 4-0 -substituted benzyl carbocation (Scheme 1). The ketonization of the product phenol (Scheme 2B) is unfavorable by ca. 19 kcal/mol.1,2... 

Kresge and coworkers, and McClelland et al.39 have generated o-quinone methide,50,5 -quinone methide,52 and related simple quinone methides as products of photolytic cleavage of 2-hydroxybenzyl and 4-hydroxylbenzyl derivatives.53 58 The results of studies on the mechanism for nucleophile addition to these simple quinone methides are summarized in latter sections of this chapter. 

The enzymes used to generate reactive quinone methides often undergo inactivation by addition of this electrophile to essential nucleophilic amino acid side chains of the protein catalyst. This is a type of suicide enzyme inhibition.80 This was observed for the acid phosphatase and ribonuclease catalysts used to generate 43.76 79 Alkaline phosphatase has been used to remove the phosphate protecting group from a derivative of an o-difluoromethyl phenyl phosphate that was covalently attached to a solid support. Breakdown of the immobilized 4-hydroxybenzyl difluoride gives an immobilized quinone methide that, in principle, will react irreversibly with proteins and lead to their attachment to the solid support.81... 

One interesting property of quinone methide 63 is that the terminal carbon of the extended conjugated system lies in both an extended quinone methide (carbons marked by +) and an extended enol (carbons marked by ). This carbon reacts as both a base in undergoing protonation to form a quinone (upper pathway, Scheme 30A) and a Lewis acid in undergoing addition of nucleophilic... 

The quinone methide carbon of 71 is also the terminal carbon of an extended enol, and therefore reacts as both a nucleophile and electrophile (Scheme 32). This carbon shows a higher relative reactivity with electrophiles compared with nucleophiles than is observed for the corresponding terminal quinone carbon of mitomycins (Scheme 30A).73 Furthermore, the addition of nucleophiles to 71 is readily reversible, but the nucleophile adduct can be trapped by reoxidation to... 

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