Pyridines arylation

Displacement reactions with oxygen nucleophiles are of potential commercial interest. Alkaline hydrolysis provides 2-fluoro-6-hydroxypyridine [55758-32-2], a precursor to 6-fluoropyridyl phosphoms ester insecticides (410—412). Other oxygen nucleophiles such as bisphenol A and hydroquinone have been used to form aryl—pyridine copolymers (413). 

One of the earliest syntheses of lavendamycin methyl ester, however, did not employ either the Pictet-Spengler or the Bischler-Napieralski reactions for construction of the /J-carboline ring system. Instead, a palladium-promoted ring closure of aryl pyridine 36 (Fig. 12) was used to prepare /1-carboline 37 by Boger and coworkers [35]. Unfortunately, stoichiometric palladium was found to be necessary, in this case 1.5 equivalents of the tetrakis(triphenylphosphine)palladium(0) being used. Friedlander condensation with aldehyde 38 in the presence of benzyltrimethylammonium hydrox-... 

Recently, a facile synthesis of substituted 2-aryl pyridine ligands was reported by Lohse et al. [293], DuPont researchers have also successfully synthesized a series of fluorine-substituted Ir complexes based on these same families of ligands using a simplified synthetic approach (Scheme 3.79) [294],... 

More recently, Shen et al. reported on a green and efficient three-component one-pot synthesis of 2-aryl-pyridines with the same starting materials as the Hanztsch reaction, under solvent-, catalyst-, and heat-free conditions. This methodology does... 

Pyridine reacts with lithium alkyls and aryls under rather vigorous conditions (e.g. xylene at 100°C) to afford 2-alkyl- and 2-aryl-pyridines. The reaction proceeds by way of the corresponding dihydropyridines (e.g. 275 or a tautomer), and these may be isolated at lower temperatures. The less reactive Grignard reagents give poorer yields of the same products. 

A convenient method for preparing vinylated or arylated pyridines on insoluble supports is palladium-mediated cross-coupling. The Heck, Suzuki, and Stille reactions have been successfully used for this purpose (Table 15.22). The conditions are essentially the same as those used for the related coupling of arenes (see Section 5.4). 

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 reactivity of ketones toward aryllead(iv) triacetates is quite different from the reaction of these ketones with lead(iv) tetraacetate, which gives the a-acetoxyketones. Under the usual conditions for arylation (pyridine, CHCI3), simple ketones remain unaffected. Only ketone enolates and some specially activated ketones have been successfully... 

Hexamethylditin is a suitable reagent for Pd-catalyzed metallation of aryl-halides to furnish aryltin compounds that in turn can react in Stille couplings with aryl halides to form biaryl derivatives. Hitchcock and coworkers [ 126] have shown that 2-pyridyl triflate and (hetero)aryl bromides can be coupled to 2-(hetero)aryl pyridines 174 in moderate to good yields (Scheme 66). The underlying principle of this heterocoupling of two aryl (pseudo)hahdes is the selective stannylation of the triflate that is undergoing a faster oxidative addition to the Pd(0) complex than the bromide. 

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. ... 

Selective lithiation of alkyl- or aryl-pyridines is the key to the synthesis of a range of new phosphinopyridine ligands, e.g., (5), (6), and a fused phosphinomethylpyridinoferrocene. A similar approach has been used in the synthesis of chelating phosphino-oxazoline ligands, e.g.,... 

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,... 

The arylated pyridine N-oxides could easily be reduced to give arylated pyridines. This methodology proceeded well with substituted diazine-N-oxides and also a wide range of electron-rich and electron-deficient aryl iodides, bromides, and chlorides [77b], The second arylation in monoarylated pyridine N-oxides (117) was further achieved selectively in the 6-position when using an inexpensive copper catalyst (Scheme 9.37) [79]. 

A 2,4,6-trisubstituted pyridine (5) also results from the reaction of the dianion of 2-methylpropene (4) with two molecules of benzonitrile (Scheme A new route to 2-aryl-pyridines is discussed on p. 273. 

Fusion of the 3-aryl-cyclopent[e][l,2]oxazines (374) at 200—280 °C gives 2-aryl-pyridines (375) in 40—80% yield a plausible mechanism is depicted in Scheme 145. Acid-catalysed ring-opening takes a quite different course, ring-contraction occurring (Scheme 146). ... 

Figure 7.40 Synthesis of fluorinated 2-(aryl)pyridines 111 and iridium complexes 112.

The barriers to rotation of a series of 2-(2 -substituted-aryl)-pyridines 290 were also determined by DNMR (Table 4). All fell within the range 57-68 kj mol and the authors claimed that a clear dependence on the steric bulk of the ort/zo-substituents was observed. Interestingly, the barrier for 2-(2-iodophenyl)-3-ethyl-6-methylpyridine was reported lower than the barrier for the 2-bromo analogue. 

A one-pot, three-component synthesis was reported to give the 2-aryl-pyridines 144 in good to excellent yields under solvent-, catalyst-, and heat-... 

Mechanistic studies revealed a significant kinetic isotope effect (kn/ko = 4.2) which excluded an electrophUic palladation pathway (unless the deprotonation is rate-limiting). A CMD process was proposed as a plausible C—H activation route as illustrated in Scheme 36. The superior activity of pyridine over benzene is attributed to the initial coordination of the Pd metal via the N(sp ) of the pyridine ring. The authors assumed that subsequent reorientation of the pyridine to bind with its Tt-system promotes the C3-H activation via CMD (after all, the C3-position of pyridine is expected to be the most electron-rich and therefore less favorable for CMD) (2013JOC8927). An aryl-Pd species (C) is formed which undergoes oxidative addition with an aryl halide to form Pd -intermediate D. Selective C3-arylated pyridine is formed upon reductive elimination from intermediate D. 

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... 

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