Phosphine ligand-free direct

Scheme 21 Ruthenium-catalyzed phosphine ligand-free direct arylation...

While this protocol relied on the in situ generation of the relevant phosphite for catalytic hydroarylation reactions, Murai and coworkers developed effective methodologies for the direct use of Lewis-basic substrates, such as acetophenone 20 (Scheme 9) [18, 59], Thereby, regioselective ruthenium-catalyzed anti-Markovnivkov alkylations and alkenylations were accomplished using alkenes or alkynes [60] as substrates, respectively. Recently, an extension of this protocol to terminal alkynes was reported, which involved a phosphine ligand-free catalytic system (see below), along with stoichiometric amounts of a peroxide [61]. 

More recently, a phosphine ligand-free ruthenium-catalyzed direct arylation with aryl bromides as electrophiles was disclosed. Notably, the use of inexpensive RuCl3(H20)n as catalyst in NMP as solvent allowed for economically attractive C-H bond functionalizations of pyridine, oxazoline and pyrazole derivatives, also with more sterically hindered orfftosubstituted aryl bromides as electrophiles (Scheme 21) [79, 80],... 

However, efforts were also directed to the development of phosphine-free catalysts. For example, the ligand-free Pd(OAc)2 promoted Suzuki reaction in water was reported using microwave heating. In this way, a low palladium loading (0.4 mol.%) was required and the cross coupling proceeded quickly (5-10 min reaction time), using boronic acids and aryl iodides, bromides and chlorides. 

Transition metal catalyzed processes are useful tools for the synthesis of functionalized thiophenes. Thus for instance, a phosphine-free, palladium catalyzed coupling protocol for the synthesis of 2-arylbenzo[d]thiophenes from various 3-substituted benzo[6]thiophenes and aryl bromides or iodides has been reported <04T3221>. Likewise, 2,2 -bithiophenes have been 5,5 -diarylated directly with aryl bromides in the presence of Pd(OAc)2, bulky phosphine ligands and CS2CO3 <04T6757>. A series of electron-deficient and relatively electron-rich benzo[6]thienyl bromides have been shown to participate in palladium catalyzed amination reactions, as exemplified by the interesting conversion of 63 to the tetracyclic system 64 upon reaction with 2-aminopyridine 65 <04EJO3679>. 

Subsequently, it was found that the use of [RhCl(coe)2]2, along with an electron-poor phosphine ligand and CsOPiv as base, allowed for the direct arylation of N—H free pyrroles when employing aryl iodides as electrophiles (Scheme 9.15) [27]. Interestingly, this protocol also proved appHcable to the direct arylation of (aza)indoles. 

This initial phase is followed by removal of the remaining phosphine ligands either as free PPI13 in solution (pathway I) or through direct transfer of PPI13 to closely associated AuClCPPhs) (pathway II). 

The speciation of the Pd(OAc)2 catalyst in such reactions is a key point. For example, Hartwig and Tan have shown that the Pd(OAc)2-catalyzed direct aryla-tion of 2-bromotoluenes and benzene proceeds more efficiently in DMA solvent in the absence of added phosphine ligands [54]. A preformed dianionic dimer, [ArPdBr2]2 , was also active. B3LYP calculations showed that C-H activation of benzene at Pd(Ph)(K -OPiv)(DMA) has a computed free energy barrier of 31 kcal mol" compared to a barrier of 42 kcal mol at Pd(Ph)(K -OPiv)(P Bu3). 

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