Electron-deficient heteroarenes

Arenes and heteroarenes which are particularly easy to metalate are tricarbo-nyl( 76-arene)chromium complexes [380, 381], ferrocenes [13, 382, 383], thiophenes [157, 158, 181, 370, 384], furans [370, 385], and most azoles [386-389]. Meta-lated oxazoles, indoles, or furans can, however, be unstable and undergo ring-opening reactions [179, 181, 388]. Pyridines and other six-membered, nitrogen-containing heterocycles can also be lithiated [59, 370, 390-398] or magnesiated [399], but because nucleophilic organometallic compounds readily add to electron-deficient heteroarenes, dimerization can occur, and alkylations of such metalated heteroarenes often require careful optimization of the reaction conditions [368, 400, 401] (Schemes 5.42 and 5.69). 

C—H bond arylations of electron-deficient heteroarenes, such as azines, remain highly challenging. An elegant and versatile solution was recently elaborated, however, through a redistribution of electron density in the starting pyridine by chemical modification [77, 78]. It was found that pyridine N-oxides smoothly underwent regioselectively palladium-catalyzed direct arylations with a variety of aryl bromides (Scheme 9.36) [77a]. 

However, for the preparation of compounds with Ar-HetAr or HetAr-HetAr bonds bearing 3-, 4- or 5-substituted electron-deficient heterocyclic moieties, direct arylations using halogenated electron-deficient heteroarenes as electrophiles are usually superior. Selected examples of such couplings are summarized in Table 9.1. 

Table 9.1 Selected arylation reactions of (hetero)arenes with halogenated electron-deficient heteroarenes (where necessary arrows indicate the position of C—H bond functionalization).

Rhodium-catalyzed C2-heteroarylation of IH-indoles and IH-pyrroles with both electron-rich and electron-deficient heteroarenes was developed by You and Lan (Scheme 56a) (2013CSC1964). An impressive set of heteroarenes including substituted (benzo)thiophenes, (benzo)furans. 

Regioselectivity for direct arylation of electron-deficient heteroarenes ... 

The C-H/C-X coupling between electron-rich or -neutral heteroarenes such as indoles, thiazoles, furans, and 1,3-azoles with aryl hahdes have been described frequently in the literature (see earlier discussion). However, the couphng of electron-deficient heteroarenes such as pyridines has remained Hmited due to their low reactivity toward electrophilic metalation as well as CMD processes. Furthermore, 2-metallaazines are generally unstable and incompatible with the reaction conditions, although examples of such cross-coupling reactions (C-M/C-X coupling) exist. 

In 2009, Chatani and Tobisu [180] found that the C-H arylation of electron-deficient heteroarenes such as quinolines and pyrazines can be achieved with diarylzinc reagents in the presence of a Ni /PCyj catalyst. In 2010, Zhang... 

In 2010, Baran reported a promoted (20 mol%) C-H/C-B coupling of electron-deficient heteroarenes, and this coupHng reaction was applied to the arylation of complex molecules such as quinine (136) [182a] (Scheme 17.39). They also reported an intramolecular C-H/C-B coupling for the synthesis of benzofurans using similar conditions [182b]. 

Suzuki [201] reported in 2007 that pyridines, which are electron-deficient heteroarenes, could undergo a homocoupling by dinuclear ruthenium complexes. For example, Cp Ru( a-H)4RuCp and (Cp Ru)2(]i.-PMe2)(]i.-H)( a- ) 7 -C5H 5) [202] promote the dimerization of 4-methoxypyridine to give 4,4 -dimethoxy-2,2 -bipyridine. Although the reaction suffers some limitations such as stoichiometric Ru complexes, high temperature, and narrow substrate scope, this is so far the only report in which simple pyridines can be homocoupled at their C-H bonds. 

Keywords Electron-deficient heteroarenes, triazenes, silver nitrate, potassium persulfate, trifluoroacetic acid, dichloromethane-water (3 5), room temperature, open-flask C-H functionalization, C-arylation, substituted heteroarenes... 

O Hara F, Blackmond DG, Baran PS. Radical-based regioselective C-H functionalization of electron-deficient heteroarenes scope, tunabihty, and predictability. JAm Chem Soc. 2013 135 12122-12134. 

Pyridine, an electron deficient heteroarene is difficult to arylate through direct and selective C—H arylation. The presence of the Fe-MCPA combination enables products to form with high regioselectivity in this case. In other words, the methodology offers an opportunity to directly arylate electron-deficient heteroarenes. 

Direct Arylation, The direct functionalization of electron-deficient heteroarenes, such as pyridines, is a challenging process. Instead, methodologies have been developed that employ pyridine (V-oxides or IV-iminopyridinium ylides, in the presence of Pd(OAc)2 and a bulky phosphine ligand (eqs 138 and 139). The coupling partners involve a variety of aryl halides and triflates, and the reaction conditions can be extended to other azine-derivatives. Both the JV-oxide and pyridinium ylide moieties can be deprotected under reductive conditionsAryl tosylates have also been reported as good coupling partners for pyridine JV-oxides. ... 

Just before Cho s report, Nagib and MacMillan reported a high-impact work on direct C—H trifluoromethylation of arenes by photoredox catalysis [79]. The use of [Ru(phen)3]Cl2 as photocatalyst and CF3SO2CI (18a) as a CF3 source enables the reaction with the broad scope with respect to the arenes, i.e., electron-rich/electron-deficient heteroarenes and unactivated arenes, in the absence of sacrificial electron... 

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