Pyridines direct arylations

Palladium-catalysed directed C-H oxidation with (diacetoxy)iodobenzene of a series of meta -substituted aryl pyridine and aryl amide derivatives resulted in the formation of the corresponding acetoxy compounds. The reactions generally proceed with high levels of regioselectivity for functionalization of the less sterically hindered ortho-C-H bond.144 The mechanism shown in Scheme 4 has been proposed for the oxidation of 2,6-dimethylphenol with (diacetoxyiodo)benzene for the formation of 3,5,3, 5 -tetramethyl-biphenyl-4,4 -diol, via C-C coupling.145... 

The alkyllithium reagents to be used in tandem reactions can be prepared by direct alkylation or by an aldol reaction involving nucleophilic addition of the alkyllithium as the first step. Several complex heteroaromatic compounds, which can serve as pivotal intermediates in synthetic strategy of biologically active species, could be synthesized by this procedure. The preparation of polysubstituted pyridines has been an active research area for many years181. The synthesis of 2-alkyl- or 2-aryl-5-hydrazinopyridines 327 has never been performed directly from pyridine. The reported methods involve several steps... 

Alkyl or aryl groups may be joined to pyridine compounds (1) through an active methyl group jn the alpha or gamma position, (2) directly at a nuclear carbon atom, or (3) at the nitrogen atom to form quaternary alkyl-or aryl-pyridinium salts. A comprehensive discussion of the alkyl- and aryl-pyridines made by these routes has been presented. ... 

The coupling reaction of arylboronic acids with aryl halides offers a direct and excellent route for the synthesis of a variety of biaryls. The same type of reaction proceeds with pyridylborane derivatives to provide an efficient alternative for the arylated pyridines as well. For example,... 

Perfluoroarenes were also found to be highly reactive coupling partners in intermolecular direct arylation [68, 69]. A wide range of aryl halides can be employed, including heterocycles such as pyridines, thiophenes, and quinolines. A fluorinated pyridine substrate may also be cross-coupled in high yield and it was also found that the site of arylation preferentially occurs adjacent to fluorine substituents when fewer fluorine atoms are present. Interestingly, the relative rates established from competition studies reveal that the rate of the direct arylation increases with the amount of fluorine substituents on the aromatic ring. In this way, it is inversely proportional to the arene nucleophilicity and therefore cannot arise from an electrophilic aromatic substitution type process (Scheme 7). 

Scheme 13 Ligand and substituent effects on pyridine V-oxide direct arylation...

A catalytic system comprising [RuCl2(rf-CJI6) 2 (11) and PPh3 was disclosed by Oi, Inoue and coworkers for direct arylations of pyridine derivatives using aryl bromides as electrophiles (Scheme 18) [72],... 

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],... 

Campeau L-C, Rousseaux S, Fagnou K (2005) A solution to the 2-pyridyl organometallic cross-coupling problem regioselective catalytic direct arylation of pyridine V-oxides. J Am Chem Soc 127 18020-18021... 

Berman AM, Lewis JC, Bergman RG, Ellman JA (2008) Rh(I)-catalyzed direct arylation of pyridines and quinolines. J Am Chem Soc 130 14926-14927... 

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]. 

Scheme 9.36 Palladium-catalyzed direct arylation of pyridine N-oxide (115).

Scheme 9.37 Copper-catalyzed direct arylation of the monoarylated pyridine N-oxide 117.

Direct phenylation of pyridine was accomplished with a heterogeneous palladium catalyst in the presence of zinc and water, albeit in only moderate yield [80]. In contrast, 2,3,5,6-tetrafluoropyridine (119) can easily be directly arylated with aryl bromides or chlorides such as 52 as electrophiles, furnishing substituted products in high yields (Scheme 9.38) [72]. 

A new approach for direct arylation of pyridine W-oxides with arylboronic acids through C-H functionalization has been developed (Scheme 45) [99]. This reaction can be performed at room temperature using catalytic silver (I) nitrate in the presence of potassium persulfate, thus giving 2-aryl derivatives of pyridine W-oxides. 

Rhodium-catalyzed direct arylations of 2-aryl pyridines were efficiently accomplished with arylstannanes through chelation-assistance (Scheme 9.3) [14]. This report constitutes an early example of a metal-catalyzed direct arylation with an... 

Highly efficient rhodium-catalyzed direct arylations were accomplished through the use of 2,2, 6,6 -tetramethylpiperidine-N-oxyl (TEMPO) as terminal oxidant [17]. Thereby, a variety of pyridine-substituted arenes was regioselectively functionalized with aromatic boronic acids (Scheme 9.5). However, in order for efficient catalysis to proceed, 4equiv. of TEMPO were required. The use of molecular oxygen as terminal oxidant yielded, unfortunately, only unsatisfactory results under otherwise identical reaction conditions. However, a variety of easily available boronic acids could be employed as arylating reagents. 

Scheme 9.5 Rhodium-catalyzed direct arylation of pyridine 1 with boronic acid 10.

The use of aryl tosylates as electrophiles is attractive, because they can be prepared from readily available phenols with less-expensive reagents than those required for synthesis of the corresponding triflates. Importantly, tosylates are more stable towards hydrolysis than triflates, yet significantly less reactive as electrophiles. As a result, protocols for traditional cross-coupHng reactions were only recently developed (see Chapter 2). In contrast, catalytic direct arylations with aryl tosylates were not reported until recently. Interestingly, a rathenium complex derived from heteroatom-substituted secondary phosphine oxide (HASPO) preligand 78 [40] allowed for direct arylations with both electron-deficient, as well as electron-rich aryl tosylates [41]. As pronucleophiles, pyridine, oxazoline and pyrazole derivatives could be efficiently functionalized. Selective mono- or diarylation reactions could be accomplished through the judicious choice of the... 

Scheme 9.26 Ruthenium-catalyzed phosphine ligand-free direct arylation of pyridine 1.

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