The Formation of 2,2-Biaryls

The formation of trace amounts of 2,2 -bipyridine following reaction between pyridine and ammonia in the presence of a variety of catalysts led Wibaut and Willink to develop a method for the preparation of 2,2 -bipyridine from pyridine under the influence of a nickel-alumina catalyst. Using a pyridine-to-catalyst ratio of 10 1, temperatures between 320° and 325°C, and pressures between 42 and 44 atm, 2,2 -bipyridine was formed in yields of 0.30-0.67 gm per gram of catalyst. This method w as later applied to -picoline, to quino-line, - and to some of its derivatives,  

In 1960 Rapoport and his co-workers found that some 2,2 -biquinoline is formed when quinoline w as used as a solvent for dehydrogenations in the presence of palladiuin-on-carbon catalyst, and they showed that several related bases (including pyridine) gave 2,2 -biai yls when refluxed at atmospheric pressure with a 5% pal-ladium-on-carbon catalyst. With a pyridine-to-catalyst ratio of 10 1, 11% conversion of pyridine to 2,2 -bipyridine was observed after heating for 24 hr. 

Rapoport s findings have been confirmed in the authors laboratory where the actions of carbon-supported catalysts (5% metal) derived from ruthenium, rhodium, palladium, osmium, iridium, and platinum, on pyridine, have been examined. At atmospheric pressure, at the boiling point of pyridine, and at a pyridine-to-catalyst ratio of 8 1, only palladium was active in bringing about the formation of 2,2 -bipyridine. It w as also found that different preparations of palladium-on-carbon varied widely in efficiency (yield 0.05-0.39 gm of 2,2 -bipyridine per gram of catalyst), but the factors responsible for this variation are not knowm. Palladium-on-alumina was found to be inferior to the carbon-supported preparations and gave only traces of bipyridine, 

Whittle, Ph.D. Thesis, Adelaide, 1962 W. H. F. Sassc and C. P. Whittle, Auslmlmn J. Chem. In press. 

Other factors which are known to lower the yield of 2,2 -bipyridine include dilution of the pyridine with a solvent (such as xylene) and the presence of pyrroles. The formation of pyrroles in the reaction, and the accumulation of 2,2 -bipyridine, are no doubt responsible for the fact that the production of 2,2 -bipyridine ceases after about 50 hr. The catalyst can be used for longer periods only if the reaction is carried out under conditions of continuous flow, or if the products of the reaction are removed as they are formed. 

In addition to the Raney nickel catalysts, Raney catalysts derived from iron, cobalt, and copper have been examined for their action on pyridine.15 At the boiling point of pyridine, degassed Raney iron gave only a very small yield of 2,2 -bipyridine but the activity of iron in this reaction is doubtful as the catalyst was subsequently found to contain 1.44% of nickel. Traces of 2,2 -bipyridine (detected spectroscopically) were formed from pyridine and a degassed, Raney cobalt catalyst but several Raney copper catalysts failed to produce detectable quantities of 2,2 -bipyridine following heating with pyridine. 

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Decomposition of this equilibrium mixture with catalytic amounts of CuOTf affords a mixture of all three possible biaryls. The formation of the unsymmetrical biaryl 2-Me2NCH2C6H4C6H4Me-4 can only be explained by the occurrence of aggregated copper species in which both the C6H4CH2NMe2-2 and the C( H4Me-4 groups are bound to the same copper core [77]. It was furthermore observed that the ratio of the formed biatyls is not statistical, which points to significant differences in the thermodynamic stabilities of the various mixed aggregates present in solution. 

An illustrative example is the formation of the symmetric biaryl from the reaction between CuC6H4NMe2-2 and IC6H4NMe2-2, which has been studied in detail in the authors laboratory [95]. When this reaction is carried out in benzene as a solvent, the reaction stops when one third of the original organocopper compound has been consumed (Eqn. 1 in Scheme 1.20). 

Recently, the formation of unsymmetrically substituted biaryls from simple arenes was achieved with a catalytic system consisting of [Pd(0Ac)2]-CF3C02H and K2S2Og under mild reaction conditions (Scheme 9.50) [128], The chemo- and regioselec-tivities of these reactions were controlled by the use of an excess of the less reactive coupling partner as solvent [129]. 

Several products other than 2,2 -biaryls have been isolated following reaction of pyridines with metal catalysts. From the reaction of a-picoline with nickel-alumina, Willink and Wibaut isolated three dimethylbipyridines in addition to the 6,6 -dimethyl-2,2 -bipyridine but their structures have not been elucidated. From the reaction of quinaldine with palladium-on-carbon, Rapoport and his co-workers " obtained a by-product which they regarded as l,2-di(2-quinolyl)-ethane. From the reactions of pyridines and quinolines with degassed Raney nickel several different types of by-product have been identified. The structures and modes of formation of these compounds are of interest as they lead to a better insight into the processes occurring when pyridines interact with metal catalysts. 

A general method for the Pd-catalyzed cross-couplings of alkyl- and arylzinc chlorides with aryl, heteroaryl, and vinyl chlorides was reported by Dai and Fu.420 They determined that the commercially available and air stable complex Pd(PBut3)2 catalyzed these reactions leading to the formation of an sp2)C - sp2)C bond (Scheme 164). Remarkably, bulky biaryls with two, three, or even four 0/7/fo-substituents (e.g., 323) were obtained in very high yields (76-96%). 

The formation of oxygen heterocycles through carbon-oxygen bond formation was also reported. Substituted 2-(o-halophenyl)-ethanols were converted to dihydrobenzofuranes using palladium and Buchwald s bulky biaryl-type ligands (3.43.). The reaction was also efficient in the formation of six and seven membered oxygen heterocycles.53... 

An alternate approach to the formation of pyridylboronic acids is the cross-coupling of a halopyridine with a diboronate ester (usually bis(pinacolato)diboron, 7.7.)9 The analogous reaction of 2-chloropyridine led to pyridine formation through protodeboronation. The product of the reaction, either after hydrolysis to the boronic acid or in the ester form, can be further reacted with another aryl halide to give a biaryl. In certain cases the reaction might also be carried out in a one-pot manner.10... 

Table 2 contains some examples of TTN oxidative coupling reactions. These examples show that the reaction can often tolerate unprotected amino add side chains, and that both 14- and 17-membered cycloisodityrosines can be obtained. In addition, the TTN oxidative coupling has been employed in the formation of 16-membered cyclic biaryl ethers of the type found in vancomycinJ20,21 The drawbacks of TTN oxidative coupling are the low yields, the formation of byproducts, and the need for additional transformations to arrive at the cycloisodityrosine target. 

As mentioned in Section 8.2, organopalladium(II) complexes can react with organyl halides to yield products of cross-coupling. The formation of large amounts of symmetric biaryls as a result of homocoupling of the aryl halide is often observed during... 

The electrophilic thallation path involves [T1(TFA)2]+ as the active electrophile which forms a jt-complex with the substrate [16, 31]. Single electron transfer from electron-enriched polymethylarenes can be significant, leading to the formation of biaryls and side-chain thallated products [31]. The electron transfer path during electrophilic metalation is much more characteristic of T1(TFA)3 than Hg(TFA)2 [16], A review article [29] includes useful analysis of mechanistic features of aromatic thallation with T1(TFA)3 and some other Tl(III) reagents, including the even more electrophilic triflate. 

Chelation-assisted C-H/olefin coupling can be applied to the atroposelective alkylation of biaryl compounds. The reaction of 2-(l-naphthyl)-3-methylpyri-dine with ethylene using [RhCl(coe)2]2 where coe is cyclooctene, and PCy3 results in the formation of an ethylation product in 92% yield (Eq. 21) [20]. In place of the PCy3 ligand, the use of (R) - (1 - [ (S) - 2- diphenylphosphino ] ferro-cenyl)ethyl methyl ether [(R),(S)-PPFOMe] leads to the atropselective alkyla-... 

Biaryls,l Biaryls can be prepared by oxidative coupling of arenes with palladium(II) compounds, but the coupling is not regioselective. Regioselectivity is considerably improved by use of TTFA as oxidant and only catalytic amounts of Pd(OAc)2. Formation of 4,4 -biaryls is favored from arenes substituted with either electron-donating or moderately electron-withdrawing substituents. The first step is thallation to form ArTl(OCOCF3)2. 

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