Intramolecular electrophilic phenol rings

The imine salt is perfectly placed for an intramolecular electrophilic aromatic substitution by the electron-rich dihydroxyphenyl ring. This closes the isoquinoline ring in a Mannich-like process (Chapter 27) with the phenol replacing the enol in the pyrrolidine alkaloid biosynthesis. 

Both benzo[fc]furans and benzo[fc]thiophenes can be obtained from the phenol or thiophenol respectively, by O-Zi -alkylation with a bromoacetaldehyde acetal and then acid-catalysed ring closure involving intramolecular electrophilic attack on the ring. 

The key step in the biosynthesis of morphine involves the oxidative phenolic coupling of reticuline (31) to salutaridine (32). This step can be viewed mechanistically as (1) oxidation of the two aromatic rings to phenoxy radicals followed by an intramolecular radical-radical coupling or (2) oxidation of one ring to a radical cation or cation, followed by an intramolecular electrophilic aromatic reaction. This process is very important in the biosynthesis of a number of natural products, and is a process that nature has used to crosslink peptides containing aromatic residues. The biosynthesis of morphine continues with reduction of salutaridine (32) to salutaridinol (33) followed by an intramolecular Sn2 reaction to give thebaine (34). Dienol ether hydrolysis to codeinone (35), reduction of the ketone to codeine (3) and 0-demethylation completes the biosynthesis of morphine (1). 

We have suggested (43) that collapse of the 4a-hydroperoxide via intramolecular nucleophilic attack ofN(5) on the peroxide could generate the three-membered oxaziridine ring (37) (Scheme 12). Should such an oxaziridine prove to be electrophilic, the oxidation of the phenolic substrate would be envisaged proceeding as in Scheme 16. 

Phenols add intramolecularly to Michael acceptors. " Under acidic conditions, a one-pot sequence starts with initial electrophilic acetylation of the activated aromatic ring and is followed by cyclization." With an appropriate leaving group in the /f-position (OMe. or other amines such as in the unsaturated carbonyl compound (e.g., 4) is formed. Other approaches to pyroncs include the self-condensation of protected //-hydroxy acrylates,intramolecular aldol reactions followed by condensation,thermal cycli-zations of unsaturated ()-chloro esters,and an iodo-cyclization-elimination sequence w th Michael acceptors.Oxymercuration of an unsaturated alcohol is an alternative cyclization approach to tetrahydropyrans. 

In view of the various types of Pd-catalyzed intermolecular a-substitution of carbonyl compounds discussed above, it might readily be expected that their intramolecular versions can proceed satisfactorily to produce cychc compounds, provided that there is not an excessive ring strain in the cyclic structure to be formed. Indeed, ketones, esters, amides, nitriles, imines, enamines, and phenols containing haloaryl, haloalkenyl, and related electrophilic groups have been converted to the corresponding cyclic compounds under the influence of Pd catalysts, as detailed below. 

Early examples of this reaction involved cyclizations of 4-substituted phenols tethered to alkyl sulfonates and halides [3]. CycMzalions involving carbonyl electrophiles (aldehydes, ketones) and imines have been reported as well, but esters are not sufiSciently electrophilic to react [2]. Subsequent studies established that the facility of these so-called Ai-n cyclizations was strongly affected by the size of the newly formed ring in the order 3>5>6 >4. Since the vast majority of alkylative dearomatizations involve intramolecular cyclizations (thereby avoiding competitive 0-aDcylation reactions), stereoelectronic effects operative in the transition states (resembling the TS of an Sjj2 reaction) are crucially important. These sometimes subtle effects can result in differential reactivity of structurally similar substrates [4]. 

A novel intramolecular alkylation using a spiroketal (14) with BFj.OEt, in THF at reflux forms the benzene-fused 8-oxabicyclo[3.2.1]octane ring system (15) in satisfactory yield. IV-Tosylpipecolinic acid (16) in the presence of sulfuric acid in benzene forms the unexpected aromatized derivative (17) in 18% yield and the mechanism is suggested to involve the reaction of intermediate (18) with benzene to form (19). Cumyl and r-butyl hydroperoxides have been used for the electrophilic alkylation of activated aromatic substrates, mainly phenols and phenol ethers.The hydroperoxides behave differently as far as catalysis and regioselectivity are concerned. The latter is believed to be explicable by steric and reactivity/selectivity considerations. Electrophilic r-butylation may be followed by radical reactions due to the r-butyl... 

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