Polycyclic arenes, formation

Apart from the construction of phenanthrenes, carbene complexes have also been used for the synthesis of more extended polycyclic arenes. An unusual dimerization of chromium coordinated ortbo-ethynyl aryl carbenes results in the formation of chrysenes (Scheme 37) [81]. This unusual reaction course is presumably due to the rigid C2 bridge that links the carbene and alkyne moieties, and thus prevents a subsequent intramolecular alkyne insertion into the metal-carbene bond. Instead, a double intermolecular alkyne insertion favored by the weak chromium-alkyne bond is believed to occur forming a central ten-membered ring that may then rearrange to the fused arene system. For example, under typical benzannulation conditions, carbene complex 97 affords an equimolar mixture of chrysene 98a and its monochromium complex 98b. The peri-interactions between the former alkyne substituent (in the 5- and 11-positions) and the aryl hydrogen induce helicity in the chrysene skeleton. 

Since its original publication this procedure has been successfully used for a very wide range of both mono- and polycyclic arenes. Provided that air is rigorously excluded anhydrous conditions are not always essential as shown by the use of water-THF (4 1) for the formation of tricarbonylchromium complexes of several phenylalanine derivatives. Professor G. Jaouen reports that the method fails for oestradiol and for the relatively weakly bound condensed arenes (naphthalene, etc.), probably because THF can displace such arenes from their complexes he recommends the use of dibutyl ether-heptane in such cases. For the formation of highly sensitive complexes. 

It is sometimes assumed that every phenol metabolite indicates the formation of an arene oxide intermediate however, as discussed above, arene oxides are not obligate intermediates in the formation of phenols. This is an important distinction because arene oxides and other epoxides are reactive intermediates that can be toxic or even carcinogenic, e.g., epoxides of some polycyclic aromatic hydrocarbons. The question of whether their formation is obligatory is significant for drug design and development and has implications for toxicity as discussed in Chapter 8. 

The delocalised radical formed by protonation of the radical-anion is more easily reduced than the starting arene. For some polycyclic aromatic hydrocarbons, the redox potential for this radical species can be determined using a cyclic voltammetry technique [10]. Reduction in dimethylformamide is carried out to the potential for formation of the dianion. The dianion undergoes rapid monoprotonation and on the reverse sweep at a fast scan rate, oxidation of the monoanion to the radical can be observed. The radical intermediate from pyrene has E° = -1.15 V vs. see in dimethylformamide compared to E° = -2.13 V vs. see for pyrene,... 

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. 

Two papers have appeared concerning the Irradiation of polycyclic aromatic hydrocarbons in the presence of nitrogen dioxide to give, along with other products, nitroarenes. while arene-nitrogen bond formation Is also reported... 

Scheme 1 shows the desired Heck reaction of alkoxy-DSB 1 with 2. The formation of 3 is accompanied by two destructive pathways the reductive debromination of 1 to 4 as a side reaction and the protodesilylation to 5 as a subsequent reaction. Particularly the latter limits the reaction conditions in terms of time and temperature. The phosphine is a decisive factor in this system consisting of three reactions a fine-tuning of the reaction conditions is possible via electronic and steric effects of the substituents in the phosphine electron-rich trialkylphosphines 6 and 7 strongly favor the reduction. Fast coupling reactions were observed with tris-o-tolylphosphine 8, the chelating diphosphine dppe 9 being even more efficient in terms of turnover, yield, and suppression of side reactions. Compared with Heck reactions of polycyclic or electron-deficient arenes with 2 [21, 22], the yield of 3 is only moderate. The reactivity of bromo-distyrylbenzenes 1 and 12 -14 in the coupling reaction is controlled by the substituents on the opposite side of the n-system (Fig. 1, Table 2) a compensation for the electron-donating alkoxy groups by a cyanide (13) or exchange of donors with electronically neutral alkyl side chains strongly improves the yields.

The photochemical arene-alkene meta-cycloaddition results in the formation of a polycyclic hydrocarbon including a cyclopropane ring. 

Estrogens induce tumors in animals, a fact that probably depends on the formation of catechol-type A rings. Arene oxides and/or semiquinones may then be formed, which react as cross-linkers in the same way as polycyclic hydrocarbons, such as benzopyrene, which is oxidized in the body to a diol-epoxide. Electroreduction of the corresponding ortho-quimm to the semiquinone radical, the same product that would be formed upon oxygen oxidation of the catechol, in the presence of adenine, does indeed produce a covalent adduct in 14% yield (Scheme 3.4.5)... 

Well established is the activation of polycyclic hydrocarbons to arene oxides 3,4-benzo(a)pyrene forms several arene oxides from which a secondary metabolite, the 9,lO-dihydrodiol-7,8-epoxide has been proved highly carcinogenicIt preferentially binds to deoxyguanosine and deoxyadenosine in DNA and by a series of further still unknown events leads to the formation of cancerous cells. The microsomal epoxide hydrase converts arene oxides and epoxides to inactive dihydrodiols and therefore coijipetes with the covalent binding process ... 

The reactions of HTIB with alkenes (Scheme 3.73) can be rationalized by a polar addition-substitution mechanism similar to the one shown in Scheme 3.70. The first step in this mechanism involves electrophilic flnfi-addition of the reagent to the double bond and the second step is nucleophilic substitution of the iodonium fragment by tosylate anion with inversion of configuration. Such a polar mechanism also explains the skeletal rearrangements in the reactions of HTIB with polycyclic alkenes [227], the participation of external nucleophiles [228] and the intramolecular participation of a nucleophilic functional group with the formation of lactones and other cyclic products [229-231]. An analogous reactivity pattern is also typical of [hydroxy(methanesulfonyloxy)iodo]benzene [232] and other [hydroxy(organosulfonyloxy)iodo]arenes. 

The isolation of a stable arene oxide metabolite of naphthalene in liver microsomal incubations provided evidence for the CYP- catalyzed epoxidation on the sp carbons on a simple phenyl ring (Scheme 13). Carcinogenesis following exposure to polycyclic aromatic hydrocarbons (PAHs) such as benzo[a]pyrene is thought to arise from arene oxide formation. Arene oxides... 

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