Cyclohexadienones reactions with nucleophiles

Fig. 7-2. Potential energy E as a function of the reaction coordinate for reactions of the P-nitrogen of arenediazonium ions with nucleophiles yielding (Z)- and (is)-azo compounds, a) Reactant-like transition states (e. g., reaction with OH) b) product-like transition states (e. g., diazo coupling reaction with phenoxide ions product = cyclohexadienone-type o-complex (see Sec. 12.8).

Arenols 4 and their conjugate arenolate bases are both (a) oxygen- and (b) carbon-based nucleophiles, which react with a wide range of electrophilic reagents (Figure 3). Their reactions with soft electrophiles can lead directly to cyclohexadienone derivatives this is the case, for example, with electrophilic halogenation, which effectively occurs at the electron-rich carbon centers (4 —> 5b) [29, 30]. 

It should be noted that numerous attempts were made to engage 42, or other similar acceptor, in a Michael reaction with external nucleophiles. Unfortunately, none of these attempts produced a useful Michael adduct and most resulted in no reaction. This lack of reactivity with external Michael donors is a general problem we have experienced with other 2,5-cyclohexadienones. 

Phenols can be viewed as stable forms of enol tautomers, and phenolate anions display ambident nucleophilicity at oxygen as weU as C2/C6 and C4 (ortholpara positions). Consequently, phenolate anions are susceptible to C—C bond formation upon reaction with appropriate organic electrophiles (e.g., alkyl halides and sulfonates). When bond formation occurs at a substituted arene carbon, a quatonaty centCT is generated, which may lead to isolation of stable cyclohexadienone products and complete a net alkylative dearomatization (Scheme 15.1) [2]. 

Linearly conjugated cyclohexadienones usually photorearrange with ring fusion to a czs-diene-ketene. The reaction is reversible, so that in the absence of a nucleophile little change is observed. A good example of this type of transformation is the formation of photosantonic acid ... 

Intramolecular oxidative cyclizations in the appropriately substituted phenols and phenol ethers provide a powerful tool for the construction of various practically important polycyclic systems. Especially interesting and synthetically useful is the oxidation of the p-substituted phenols 12 with [bis(acyloxy)iodo]-arenes in the presence of an appropriate external or internal nucleophile (Nu) leading to the respective spiro dienones 15 according to Scheme 6. It is assumed that this reaction proceeds via concerted addition-elimination in the intermediate product 13, or via phenoxenium ions 14 [18 - 21]. The recently reported lack of chirality induction in the phenolic oxidation in the presence of dibenzoyltar-taric acid supports the hypothesis that of mechanism proceeding via phenoxenium ions 14 [18]. The o-substituted phenols can be oxidized similarly with the formation of the respective 2,4-cyclohexadienone derivatives. 

Disubstituted phenols such as 350 undergo PhI(OAc)2-mediated oxidation in the presence of MeOH as a nucleophile resulting in the formation of two possible cyclohexa-dienones (351 and 352) (Scheme 73). The initially formed intermediate 353 is converted to the cyclohexadienones by two plausible routes. In route A, heterolytic dissociation generates a solvated phenoxonium ion 354, which further reacts with MeOH to afford 351 and/or 352. In route B, both 351 and 352 are produced by direct attack of MeOH on the intermediate (353). In the latter case, the reaction will be strongly influenced by steric factors and a homochiral environment using chiral solvents and chiral oxidants to induce some asymmetric induction, particularly in the formation of 352. 

Oxidative dearomatization of 4-substituted phenols 222 with [bis(acyloxy)iodo]arenes in the presence of an external nucleophile provides a convenient approach to various 3,3-disubstituted cyclohexadienones 224 according to Scheme 3.92. Several examples of this reaction are provided below in Schemes 3.93-3.97. 

Recently, an oxidative dearomatization of substituted phenols followed by a desymmetrizing asymmetric intramolecular Michael addition catalyzed by the pro-linol derivative 27 has been described towards the synthesis of highly functionalized polycyclic molecules with excellent enantioselectivities [40]. As shown in Scheme 2.15, the reaction starts with an oxidation of the phenol moiety to the corresponding mera-cyclohexadienones employing PhlCOAc), mild oxidant that does not react with the aldehyde nor with the catalyst. In the presence of different nucleophiles such as, methanol, cyanide, or fluoride, intermediates 26 are formed, which suffer intramolecular Michael addition of the aldehyde moiety to afford the desired chiral products 28 with excellent diastereo- and enantioselectivities. 

Arene oxidation leading to direct C—C bond formation allows rapid assembly of complex and ste-reochemically rich carbocyclic ring systems. Crucial to the success of this approach is the identification of carbon nucleophiles that are stable in the presence of oxidation agents typically used to effect arene dearomatization. Enolates and enol ethers are problematic as these species undergo rapid oxidation under mild conditions [62]. Stabilized enolates (such as those derived from activated methylenes) exhibit greater compatibility with oxidation conditions and have been used as nucleophilic participants in intramolecular oxidative dearomatizations initiated by [Fe(CN)g] and PIDA to afford spirocyclic cyclohexadienones [63, 64]. Detailed mechanisms for these reactions have not been defined so it is unclear whether bond formation occurs through ionic or radical intermediates. 

The Kolbe reaction is mechanistically similar to the reaction of Grignard reagents with carbon dioxide. The increased electron density at G-2 or C-4 in the phenolate ion allows either carbon atom to act as a nucleophile and attack the carbon atom of carbon dioxide. Reaction at the position ortho to the oxygen atom is shown. Tautomerization of the cyclohexadienone gives the phenol. 

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