Multiple Arylation

The traditional inteimolecular Mizoroki-Heck arylation has been essentially limited to the monoarylations of olefins. By taking advantage of attractive substrate-catalyst interactions, multiple arylations have become possible by using an olefin bearing a coordinating auxiliary. In 2001, Hallberg and coworkers [15] and Itami et al. [16] independently discovered such processes. The latter processes will be discussed in the sections dealing with vinyl silanes (Sections 7.6) and vinyl sulfides (Section 7.7). 

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Palladium-catalyzed multiple arylations have been employed for the synthesis of elaborated carbocycles (Equation (42)). 

Other heterocycle analogs have been made by multiple arylations and in some cases a carbamoyl-directing group is cleaved during the reaction (Equations (140)—(142)).122 (For other multiple arylations, see Refs 122b-122d.)... 

In some cases multiple arylation products are obtained (Equation (144)). 

The palladium-catalyzed arylations of aromatic carbonyl compounds such as ketones,67,67a amides (Equation (60)),68 and aldehydes69 with aryl halides and triflates give the multiple arylation products similarly. 

Palladium-catalyzed reaction of 2-hydroxy-2-methylpropiophenone with aryl bromides shows a unique multiple arylation via successive C-C and C-H bond cleavages, giving tetraarylethanes.96 For example, the reaction of 2-hydroxy-2-methylpropiophenone with bromobenzene in the presence of Pd(OAc)2, P(/-Bu)3, and CS2CO3 gives 1,1,2,2-tetraphenylethane quantitatively, together with l,4,4-triphenyl-7-methylisochroman-3-one (13% yield) (Equation (74)). 

Charge delocalization can also be promoted by multiple aryl substitution at the metalated carbon atom. A lucid example is the Ph3C trityl anion. The central carbon atoms in [(TMEDA)LiCPh3]2 (192) and [(Et20)2LiCPh3] 37 (193) show almost ideal planar environment. The three phenyl groups cannot all be arranged in a coplanar fashion due to... 

Multiple arylations of polybromobenzenes have been conducted to generate electron-rich arylamines. Tribromotriphenylamine and 1,3,5-tribromobenzene all react cleanly with A-aryl piperazines using either P(o-tolyl)3 or BINAP-ligated catalysts to form hexamine products [107]. Reactions of other polyhalogenated arenes have also been reported [108]. Competition between aryl bromides and iodides or aryl bromides and chlorides has been investigated for the formation of aryl ethers [109], and presumably similar selectivity is observed for the amination. In this case bro-mo, chloroarenes reacted preferentially at the aryl bromide position. This selectivity results from the faster oxidative addition of aryl bromides and is a common selectivity observed in cross-coupling. Sowa showed complete selectivity for amination of the aryl chloro, bromo, or iodo over aryl-fluoro linkages [110]. This chemistry produces fluoroanilines, whereas the uncatalyzed chemistry typically leads to substitution for fluoride. 

Multiple arylations of polybromobenzenes were also conducted to generate electron-rich arylamines. Tribromotriphenylamine and 1,3,5-tribromobenzene all react cleanly with iV-aryl piperazines using either P(o-tolyl)3 or BINAP-ligated catalysts to form hexamine products [107]. Reactions of other polyhalogenated arenes have also been reported [108]. 

A few groups have carried out multiple arylation reactions to give bis-C-glycosyl compounds (Scheme 89). Schmidt et al. used their trichloroacetimidate methodology... 

Ueura K, Satoh T, Miura M (2005) Rhodium-catalyzed arylation using arylboron compounds efficient coupling of aryl halides and unexpected multiple arylation of benzonitrile. Org Lett 7 2229-2231... 

Cyclic secondary amines are, along with a few other nitrogen nucleophiles, the most unproblematic ones because they are less bulky, more nucleophUic compared to their acyclic derivatives, and less prone to P-hydride ehmination. Additionally, the problematic multiple arylation as found for ammonia or primary amines cannot occur. 

C2-Arylated 1,3-Azoles In 1998, Miura reported the first example of the catalytic C-H arylation of (benzo)azoles and thiophenes (at their C2 position) with aryl halides [98, 99a]. In the presence of catalytic Pd(OAc)2 and stoichiometric carbonate base at high temperature (140 °C), 1,3-azoles (oxazoles, N-alkylated imidazoles, fhiazoles) were coupled with various aryl bromides selectively at the C2 position. For the reactions of N-alkylated benzimidazoles, benzoxazoles, and benzothiazoles, addition of Cul was necessary to increase the yield of products. Furthermore, when N-methylbenzimidazole was used, Miura discovered that the coupling with aryl bromides proceeds without the palladium catalyst (i.e., by a copper-mediated C-H/C-X coupling of azoles with aryl halides). Thereafter, Miura enhanced the efficiency of the coupling reaction to allow for multiple arylations of azoles both C2 and C5 positions [99b]. In 2000, Rondo [100] prepared polymer-supported aryl iodides, with which the direct coupling reaction with 1,3-azoles (Miura s conditions) was conducted. 

Murai and Shibahara [123] also synthesized this target via sequential C-H arylation from a simple imidazole using their robust catalyst, [Pd(phen)2](PFg)2. Sames [125] also reported multiple arylations of simple imidazoles using his own catalytic system. 

Rhodium has been successfully used in a range of Suzuki-Miyaura type reactions. Satoh and Miura have reported the Suzuki-Miyaura-type cross-coupling of arylboron compounds with aryl halides in the presence of a rhodium-based catalyst system to produce the corresponding biaryls (Scheme 13.21). They also found, unexpectedly, that when employing benzonitrile as substrate under similar reaction conditions a multiple arylation is observed, in which nucleophilic arylation on the cyano group and subsequent ortho arylation via C-H bond cleavage is involved. 

Multiple arylations of oxazole was demonstrated with a paUa-dium/phenanthroline catalyst. Electron-deficient aryl iodides tended to provide the triarylated product, while more rich substrates furnished a mixture of products (eq 26). 

SCHEME 4 30 Synthesis of multiple aryl groups through sequential functionalizations [387],... 

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