Electron-rich aryl bromides

Indoles, pyrroles, and carbazoles themselves are suitable substrates for palladium-catalyzed coupling with aryl halides. Initially, these reactions occurred readily with electron-poor aryl halides in the presence of palladium and DPPF, but reactions of unactivated aryl bromides were long, even at 120 °C. Complexes of sterically hindered alkylmonophosphines have been shown to be more active catalysts (Equation (25)). 8 102 103 In the presence of these more active catalysts, reactions of electron-poor or electron-rich aryl bromides and electron-poor or electron-neutral aryl chlorides occurred at 60-120 °C. Reactions catalyzed by complexes of most of the /-butylphosphines generated a mixture of 1- and 3-substituted indoles. In addition, 2- and 7-substituted indoles reacted with unhindered aryl halides at both the N1 and C3 positions. The 2-naphthyl di-t-butylphosphinobenzene ligand in Equation (25), however, generated a catalyst that formed predominantly the product from A-arylation in these cases. 

A perhaps more exotic substrate for the Heck reaction is 1,2-cyclohexanedione [25], The reactivity of this molecule under Heck coupling conditions can probably be attributed to its resonance enol form. This reaction is attractive, because the literature contains relatively few examples of the preparation of 3-aryl-l,2-cyclohexane-diones. Yields varied from good to modest when classic heating and electron-rich aryl bromides were used, and reaction times typically ranged from 16 to 48 h. Similar yields were obtained under continuous microwave irradiation with a single-mode microwave reactor for 10 min at 40-50 W (Eq. 11.10) [25],... 

Inactivated aryl bromides do not react with /-PrMgCl in a sufficient rate even at temperatures as high as room temperamre. However, the presence of 1 equivalent of LiCl in the reaction mixmre enhances the rate of the exchange reaction tremendously, thus even allowing the use of electron-rich aryl bromides (equation 21). ... 

More recently, Chiu and coworkers have developed a Ni complex containing a tetradentate pyridine/NHC ligand (complex 18, Eq. 22) which catalyzes the Suzuki reaction at catalyst loadings between 1 and 3 mol% [56]. Aryl iodides, bromides, and chlorides with both electron-rich and -poor aryl rings were compatible. However, electronically poor or electronically neutral aryl bromides performed much better than did electron-rich aryl bromides. It was also found that the use of 2 equivalents of PPh3 was crucial to achieving high yields with aryl chlorides. 

In addition, electron-rich aryl bromides were better tolerated with the BINAP/ Pd-system, Eq. (65). Although NaOf-Bu is typically used as base, Prashad and co-workers recently reported that NaOMe and NaOi-Pr may also be used as well [30]. 

The 27/Pd-catalyst is considerably more reactive that the 26-based system. The new, more reactive catalyst was reported to allow the coupling of electron-rich aryl bromides with NaOf-Bu in moderate yields, Eq. (187) [149]. 

In some cases, the 6/Pd-catalyst is capable of mediating the coupling of electron-rich aryl bromides and phenols as well [152]. For example, the reaction of 3-bromoanisole shown below proceeded in 87% yield, Eq. (195). With more challenging electron-rich substrates, other bulky ligands are better suited. 

The group also reported DME in the presence of potassium tert-butoxide to be an efhcient source of carbon monoxide and dimethyl-amine in palladium-catalyzed aminocarbonylation (Heck carbonylation Scheme 25.2D). The addition of excess amines to the reaction mixture provided good yields of the corresponding aryl amides. The reaction proceeded smoothly with bromobenzene and more electron-rich aryl bromides, but not with electron-deficient aryl bromides. 

In contrast, coupling reactions with aryl chlorides and electron rich aryl bromides are not as well optimized in the fixed-bed system. For exanple, with 4-bromoanisole only 85 % conversion was observed at 80 °C after 52 h. Unfortunately, we were unable to achieve reasonable reactivity (25 % conv., 125 h, 80 °C) with an aryl chloride substrate (4-chlorobenzotrifluoride) using conditions that we previously developed for single-cycle batch reactions. In both cases, the catalyst activity seemed to erode over time and reaction stalled before conqilete conversion. The difference in reactivity conqjared to the batch studies may be attributed to the low Pd loading of the catalyst (i.e., 0.8 w/w% vs. a typical 5 w/w %) and the pre-reduced nature of the catalyst which may not be optimized for the Suzuki coupling reaction. 

Noteworthy, are the superior yields for coupling of amines with orfho-substituted halides and halopyridines. [15c] In case of the synthesis of aminopyridines the improved catalyst activity is explained by the ability of chelating ligands to prevent formation of bis-pyridyl palladium complexes that terminate the catalytic cycle. Interestingly, electron rich aryl bromides (entry 2) gave similar high yields as electron poor aryl halides (entry 1). The sterically hindered aryl bromide 1-bromo-2,5-dimethylbenzene can be coupled with A-methylpiperazine even in the presence of just 0.05 mol % palladium (entry 4). Thus, catalyst turnover numbers up to 2000 were realized for the first time. When primary amines are used, just small ammounts of double arylated products were detected. 

More recently, the use of potassium phosphate has also been reported for the a-arylation of ketones with chloroarenes. KHMDS was the most effective base for the intermolecular arylation of A Af-dialkylamides (eq 35). Higher yields were observed with KHMDS compared to LiTMP. Use of NaOr-Bu resulted in low conversion together with a high level of undesired side products, while LDA appeared to deactivate the system. Coupling of unfunctionalized and electron-rich aryl bromides with A,A-dimethylacetainide afforded a-aryl amides in moderate to good yields when the reaction was conducted with at least 2 equiv of KHMDS base. Diarylation of acetamides as well as hydro-dehalogenation of the aryl halides were side reactions that limited this process. 

HR of electron-rich aryl bromides with 1,1- or 1,2-disubstituted alkenes such as methyl methacrylate (71) and crotonate (72) proceeds at room temperature in dioxane with the same catalyst to provide 73 and 74 [26]. 

Bidentate phosphine ligands such as BINAP and DPPF were found to give much better results than P(o-Tol)3 in the reaction of A-methylaniline with electron-rich aryl bromides as shown by the following examples [7,8]. 

The terminal alkyne can also be generated in situ via copper-free Sonogashira cross-coupling of trimethylsilyl acetylene (5a) and aryl halides 6 and subsequent cleavage with TBAF, caibonylation, and cyclization (Scheme 26) (20090L(11)3210). This microwave-assisted sequence allows the rapid synthesis of the title compounds in moderate to good yields. Each compound can be easily varied with exception to trimethylsilyl acetylene. The application of electron-rich aryl bromides and iodides expectedly decreases the yields. 

Another supported system is Alper s sihca-immobilized pincer complex 49, which effects the reaction between electron-rich aryl bromides and standard alkenes using a 1 mol%... 

A majority of the carbonylations of organic halides have been conducted with aryl and vinyl halides, although reactions have been developed with benzylic halides and even purely aliphatic halides. A majority of the reactions of aryl halides have been conducted with aryl iodides, although a few reactions have been reported with electron-poor aryl bromides. Few examples of these reactions have been reported with electron-rich aryl bromides or aryl chlorides. Most of these reactions have been conducted with palladium complexes containing phosphine ligands. 

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