Arylamine electrophilic aromatic substitution

The orbital and resonance models for bonding in arylamines are simply alternative ways of describing the same phenomenon Delocalization of the nitrogen lone pair decreases the electron density at nitrogen while increasing it m the rr system of the aro matic ring We ve already seen one chemical consequence of this m the high level of reactivity of aniline m electrophilic aromatic substitution reactions (Section 12 12) Other ways m which electron delocalization affects the properties of arylamines are described m later sections of this chapter... 

Arylamines contain two functional groups the amine group and the aromatic ring they are difunctional compounds The reactivity of the amine group is affected by its aryl substituent and the reactivity of the ring is affected by its amine substituent The same electron delocalization that reduces the basicity and the nucleophilicity of an arylamme nitrogen increases the electron density in the aromatic ring and makes arylamines extremely reactive toward electrophilic aromatic substitution... 

Electrophilic aromatic substitution (Sec tion 22 14) Arylamines are very reac tive toward electrophilic aromatic sub stitution It IS customary to protect arylamines as their N acyl derivatives before carrying out ring nitration chio rination bromination sulfonation or Friedel-Crafts reactions... 

Arylamine Electrophile Product of electrophilic aromatic substitution... 

Tertiary alkylamines illustrate no useful chemistry on nitrosation. Tertiary arylamines undergo nitrosation of the ring by electrophilic aromatic substitution. 

Diazonium coupling reactions are typical electrophilic aromatic substitutions in which the positively charged diazonium ion is the electrophile that reacts with the electron-rich, ring of a phenol or arylamine. Reaction usually occurs at the para position, although ortho reaction can take place if the para position is blocked. 

Despite many applications of the iron-mediated carbazole synthesis, the access to 2-oxygenated tricyclic carbazole alkaloids using this method is limited due to the moderate yields for the oxidative cyclization [88,90]. In this respect, the molybdenum-mediated oxidative coupling of an arylamine and cyclohexene 2a represents a complementary method. The construction of the carbazole framework is achieved by consecutive molybdenum-mediated C-C and C-N bond formation. The cationic molybdenum complex, required for the electrophilic aromatic substitution, is easily prepared (Scheme 23). 

Tricarbonyliron-coordinated cyclohexadienylium ions 569 were shown to be useful electrophiles for the electrophilic aromatic substitution of functionally diverse electron-rich arylamines 570. This reaction combined with the oxidative cyclization of the arylamine-substituted tricarbonyl(ri -cyclohexadiene)iron complexes 571, leads to a convergent total synthesis of a broad range of carbazole alkaloids. The overall transformation involves consecutive iron-mediated C-C and C-N bond formation followed by aromatization (8,10) (Schemes 5.24 and 5.25). 

Using this method, the electrophilic aromatic substitution of the electron-rich arylamine 578 by the molybdenum-complexed cation 577 affords regio- and stereoselectively the molybdenum complexes 579. Cyclization with concomitant aromatization and demetalation using activated manganese dioxide leads to the carbazole derivatives 568 (8,10,560) (Scheme 5.26). 

The two key steps for the construction of the carbazole framework by the iron-mediated approach are, first, C-C bond formation by electrophilic aromatic substitution of the arylamine with the tricarbonyliron-complexed cyclohexadienyl cation and, second, C-N bond formation and aromatization by an oxidative cyclization. Application of this methodology provides murrayanine (9) and koenoline (8) in three steps and 15%, and in four steps and 14% overall yield, respectively, starting from the commercial nitroaryl derivative 601 (573,574) (Scheme 5.33). 

Catalytic hydrogenation of the nitroarene 601 afforded the corresponding arylamine 598. An electrophilic aromatic substitution of the arylamine 598 by... 

Electrophilic aromatic substitution of the arylamine 780a using the iron-complex salt 602 afforded the iron-complex 785. Oxidative cyclization of complex 785 in toluene at room temperature with very active manganese dioxide afforded carbazomycin A (260) in 25% yield, along with the tricarbonyliron-complexed 4b,8a-dihydro-3H-carbazol-3-one (786) (17% yield). The quinone imine 786 was also converted to carbazomycin A (260) by a sequence of demetalation and O-methylation (Scheme 5.86). The synthesis via the iron-mediated arylamine cyclization provides carbazomycin A (260) in two steps and 21% overall yield based on 602 (607-609) (Scheme 5.86). 

The construction of the carbazole framework was achieved by slightly modifying the reaction conditions previously reported for the racemic synthesis (614). Reaction of the iron complex salt 602 with the fully functionalized arylamine 814 in air provided the tricarbonyliron-coordinated 4b,8a-dihydrocarbazole complex 819 via sequential C-C and C-N bond formation. This one-pot annulation is the result of an electrophilic aromatic substitution and a subsequent iron-mediated oxidative cyclization by air as the oxidizing agent. The aromatization with concomitant demetalation of complex 819 using NBS under basic reaction conditions, led to the carbazole. Using the same reagent under acidic reaction conditions the carbazole was... 

Four years later, we reported an improved iron-mediated total synthesis of furostifoline (224) (689). This approach features a reverse order of the two cyclization reactions by first forming the carbazole nucleus, then annulation of the furan ring. As a consequence, in this synthesis the intermediate protection of the amino function is not necessary (cf. Schemes 5.178 and 5.179). The electrophilic aromatic substitution at the arylamine 1106 by reaction with the iron complex salt 602 afforded the iron... 

Protecting the amino group of an arylamine in this way moderates its reactivity and permits nitration of the ring to be achieved. The acetamido group is activating toward electrophilic aromatic substitution and is ortho, para-directing. 

Electrophilic aromatic substitution of 5-hydroxy-2,4-dimethoxy-3-methylaniline by reaction with the iron complex salts affords the corresponding aryl-substituted tricarbonyliron-cyclohexadiene complexes. O-Acetylation followed by iron-mediated arylamine cydization with concomitant aromatization provides the substituted carbazole derivatives. Oxidation using cerium(IV) ammonium nitrate (CAN) leads to the carbazole-l,4-quinones. Addition of methyllithium at low temperature occurs preferentially at C-1, representing the more reactive carbonyl group, and thus provides in only five steps carbazomycin G (46 % overall yield) and carbazomycin H (7 % overall yield). 

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