Friedel-Crafts coupling cyclization

Numerous investigations have centered on the trapping of anodically generated phenoxonium ions with nucleophilic centers tethered to the reacting phenol ring. Much of the early work in this area centered on anodic phenolic coupling reactions, which are essentially Friedel-Crafts type cyclizations, affording spirodienones such as (LIII), often in excellent yield [Eq. (23)] [53]. Anodic cyclizations are treated in detail elsewhere in this edition. 

The synthesis of rofecoxib can be achieved by several different routes (Drugs Fut., 1998). A highly efficient synthesis for rofecoxib was recently described (Therien et al., 2001). As illustrated in Scheme 79, acetophenon (i) is prepared according to the literature, by Friedel-Crafts acylation with thioanisole. Oxidation with MMPP (magnesium monoperoxyphthalate hexahydrate) affords the sulfone (ii), which is reacted with bromine in chloroform in the presence of a trace amount of AICI3, to give (iii). Bromoketone (iii) is than coupled and cyclized in a second step, one-pot procedure with phenylacetic acid. Firstly, the mixture of bromoacetophenone (iii) and phenylacetic acid in acetonitrile is treated with... 

Diphenylcinnoline can be prepared from benzil monophenylhydrazone in the presence of about 80% sulfuric acid (49MI21200). Synthetically more important, however, is the cyclization of mesoxalyl chloride phenylhydrazones under Friedel-Crafts conditions (61JCS2828). As outlined in Scheme 67, the starting mesoxalate phenylhydrazones are obtained by coupling diazotized aromatic amines with diethyl malonate. After conversion... 

Directed remote metalation (DreM) of biaryl amides and O-carbamates, conceptually based on the complex-induced proximity effect (CIPE) [15] provides, especially in view of their link to transition metal-catalyzed cross coupling regimens [16], general and versatile routes to fluorenones (16 —> 15, Scheme 4) [5,17] and biaryl amides (16 —> 17) [18] whose features are overriding Friedel-Crafts reactivity and yield enhancement in comparison to Suzuki-Miyaura coupling routes for highly hindered biaryls, respectively. Additional features of the O-carbamate DreM result is potential further DoM of 17 with appropriate phenol protection and cyclization to dibenzopyranones [18]. 

Synthesis of diaryl heteroarotinoids (11) and (12) [27,30,31] began with a Lewis acid-catalyzed cyclization of tertiary alcohol (34) to give dihydroben-zothiophene (36) as the sole isolated product. The chemistry of the ensuing steps was similar to that used to prepare (9) and (10) and other diaryl heteroarotinoids and involved (a) Friedel-Crafts acylation of a fused aromatic-heterocyclic system, (b) reduction of the resulting ketone to a benzylic carbinol, (c) phosponium salt formation, and finally (d), Wittig coupling to methyl 4-formylbenzoate. The free acids (13) and (14) were obtained by saponification. 

In contrast to the FVP synthesis of indenocorannulene (98) from phenyl-corannulene, the fluoro-substituted analogue 29 (X=F) turns out to be very efficient [126] (Scheme 28). Catalytic cyclization is initiated by reaction of a silyl cation with an aryl fluoride to generate a phenyl cation and, subsequently, Friedel-Crafts reaction to an intramolecular aryl coupling, flowed by deprotonation, to give 98, The enabling feature of this reaction is the exchange of carbon-fluorine for sihcon-fluoiine bond enthalpies. 

Other potentially useful reactions, similarly unexplored, involve the lateral met-allation cyclization to oxindoles, 86 —> 88, the N-to-ortho-C carbamoyl migration to anthranilamides, 86 —> 89, and the thereby facilitated further DoM chemistry to produce 90, substances that may further be used in cross-coupling reactions, for example, E = hal, B(OR)2 [133], This anionic arene chemistry has complementarity to the Friedel-Crafts reactions (for 85 and 87) and synthetic consequences for a variety of heterocyclic frameworks represented in the structures in Scheme 14.21. 

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