Intramolecular C -H arylation

Intramolecular C-H arylations have been described and are mediated by a variety of palladium complexes, affording a host of heterocyclic products. Carbazoles can be synthesized by a sequential amination/C-H functionalization process (Equation (161)). 

Scheme 16 Formal synthesis of indaziflam involving a conformationally challenging Pd°-cata-lyzed intramolecular C-H arylation...

During the past few decades, intramolecular C-H arylation of simple arenes with aryl halides has been applied to the synthesis of biological compounds such as natural products, pharmaceuticals as well as organic materials. Herein, some recent applications of intra- and intermolecular C-H arylation of simple arenes with aryl halides are described (Scheme 17.10). 

In 2011, Wu [43] applied intramolecular C-H arylation to the synthesis of highly curved buckybowls, which contain corannulene and sumanene fragments. Several polycyclic aromatic hydrocarbons (PAHs) to prepare less strained bowls have aheady been synthesized using palladium-catalyzed intramolecular arylation reactions [45]. 

As arylindole and arylpyrrole motifs are ubiquitous in natural products and pharmaceuticals [46, 47], the rapid construction of these units via C-H arylation is important in organic synthesis. Over the past few decades, numerous metal-catalyzed intramolecular C-H arylations of indoles/pyrroles have been reported however, their intermolecular counterparts have only begun to appear in the twenty-first century (with the notable exception of Ohta s result, see Scheme 17.2)... 

One representative application of indole/pyrrole C-H arylation is the total synthesis of rhazinilam developed by Trauner (Scheme 17.15) [68a]. Treatment of 60 with conditions similar to those reported by Fagnou resulted in the formation of coupling product 61 in 47% yield. After several steps, the synthesis of rhazinilam was achieved. Trauner [68b] also synthesized rhazinal, a congener of rhazinilam, by this intramolecular C-H arylation method. 

More recently, a palladium-catalyzed intramolecular C-H arylation with mesylated compounds was reported by Kalyani and co-workers. A sequential mesylation-arylation protocol using phenols as substrates vras described as well. This method allows for the synthesis of diverse heterocyclic motifs, including dibenzofurans, carbazoles, and indoles, in good yields (Scheme 2.30). The intermolecular aiylations were efficient for the coupling of azoles with electronically diverse mesylates. 

In 2010, Hocek and co-workers employed intramolecular C-H arylations as a key step in the synthesis of fused purine systems 13-substituted pur-ino[8,9- phenanthridines and 11-substituted 5,6-dihydropurino[8,9-a]iso-quinolines. Moderate yields of the products can be achieved by double C-H aiylations of 9-phenylpurines with 1,2-diiodobenzene. The consecutive Suzuki coupling of 9-(2-bromophenyl)purines with 2-bromophenylboronic acid followed by intramolecular C-H aiylation was more efficient. 

Dihydropurino[8,9-a]isoquinolines were prepared in quantitative yields by intramolecular C-H arylations of 9-(2-chlorophenethyl)purines. The novel fused heterocyclic systems of purino[8,9 /]phenanthridines and... 

The second step in the process consisted of a palladium-catalyzed intramolecular cycliza-tion followed by an intramolecular C-H arylation reaction to afford the polycyclic indoles. While only a few examples were reported, the tolerance of the first step in the process to air coupled with the availability of all the reagents makes this an attractive approach to the synthesis of this interesting class of compounds. 

With aromatic bromides as the substrates, in 2009, Gevorgyan reported a concise procedure for the synthesis of sihcon-containing oxacydes via the palladium-catalyzed intramolecular C-H arylation. And the resulted sUyl oxacydes could be subsequently desUylated into the corresponding orf/ o-arylated phenols easily (Scheme 3.2) [12]. 

Sultones are the internal esters of hydroxy sulfonic acids and sulfur analogs of lactones. The biological activities of sultones are concerned with toxicological, skin sensitization, and antiviral properties [13]. In 2009, Majumdar developed a Pd(PPh3)4-catalyzed intramolecular C-H arylation reaction of benzenesulfonic acid 2-bromophenyl esters to afford polycyclic sultones, which are generally synthesized by elimination of the corresponding hydroxyl sulfonic acid derivatives, in up to 90% yield (Scheme 3.3, path a) [14]. TBAB was found to be critical in this reaction, and no reaction occurred in the absence of this additive. An electrophilic palladation mechanism was proposed for this transformation. 

Scheme 3.3 Pd

Scheme 3.4 Pd-catalyzed synthesis of dibenzofurans via intramolecular C-H arylation.

In 2005, Trauner and coworkers reported the synthesis of rhazinilam using a palladium-catalyzed intramolecular C-H arylation of a pyrrole unit with an iodoarene (Scheme 16.12a) [24]. Treatment of compound 57 with a palladium catalyst resulted in the formation of coupling product 59 through intermediate 58. After removal of the MOM group and decarboxylation, the synthesis of... 

Scheme 16.11 An early contribution for the synthesis of a pyrrole-containing natural product by using an intramolecular C-H arylation strategy.

The palladium-catalyzed intramolecular C-H arylation of aromatic C-H bonds with haloarenes (Ar-H/Ar-X coupling, where X is halogen) is effective for the synthesis of carbazole alkaloids with amine linkers, as reported by Bedford and coworkers in 2006 (Scheme 16.16a) [34]. Buchwald-Hartwig coupling of an aryl bromide and an aniline derivative generated aryl chloride 91 in situ, which was easily cyclized under palladium catalysis to give clausine P in 80% yield. They also... 

In 2004, Harayama and coworkers reported an intramolecular C-H arylation between two heteroarenes (Scheme 16.30) [65]. The coupling precursor 146, which was synthesized by Ai-alkylation of 4-quinazolinone with 2-bromo-3-(bromomethyl)quinoline, was cyclized using catalytic Pd(OAc)2 and PPhj to give luotonin A in 66% yield. This natural product was then hydroxylated in two steps to provide luotonin B as well as rutaecarpine using the same strategy. 

Scheme 16.30 Synthesis of luotonin B and rutaecarpine using intramolecular C-H arylation.

Quinolines, Isoquinolines, Phenanthridines, and Related Compounds 16.2.7.1 Norchelerythrine (Intramolecular C-H Arylation)... 

In 2001, Harayama and coworkers demonstrated an intramolecular C-H arylation (Ar-H/Ar-X coupling) using Al-naphthylbenzamide 150 for the synthesis of norchelerythrine, a phenanthridine alkaloid (Scheme 16.32) [66]. After preparation of aryl iodide 150, Pd-catalyzed intramolecular C-H arylation was performed to afford the coupling product 151 in 96% yield. After reduction of the amide moiety in 151 and removal of the MOM group, the total synthesis of norchelerythrine was accomplished. 

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