2-Bromopyridine, reaction with palladium

While carefully isolating all products from a reaction of 2-bromopyridine 19 with palladium catalyst, bimetallic complex 148 was isolated and determined to be a pre-catalyst for the Suzuki reaction [52]. Upon examining the utility of this complex, it was found to be able to carry out Suzuki reactions, such as the conversion of 149 and 150 into 151. 

Several of the methods of synthesis of 2,2 -bipyridines have their counterpart in the preparation of 4,4 -bipyridine. The Ullmann reaction has been used to prepare 4,4 -bipyridine. Thus 4-halogenated pyridines afford 4,4 -bipyridine. Dehalogenation and dimerization of 4-bromopyridine may be accomplished too with hydrazine and alkali at 65°C in the presence of a palladium catalyst, whereas 4-chloropyridine is converted to 4,4 -bipyridine in 46% yield by reaction with alkaline sodium formate in the presence of palladium on charcoal and a surfactant. Several extensions of the Ullmann reaction have recently been reported, especially for the synthesis of substituted 4,4 -bipyridines. Thus 4-iodo-2-methylpyridine gives 2,2 -dimethyl-4,4 -bipyridine, 3-nitro-4-chloropyridine affords 3,3 -dinitro-4,4 -bipyridine, 4-bromo- or 4-iodotetrafluoropyridine gives octafluoro-4,4 -bipyridine, and 4-iodo- or 4-bromotetrachloropyridine gives octachloro-4,4 -bipyridine. Related syntheses have been de-... 

The obvious limitation of this reaction so far is in the electrophile as we have suggested naturally electrophilic enones as ideal partners for aryl or vinyl palladium o-complexes. In fact, complexation with palladium makes all alkenes electrophilic and nucleophilic addition can in principle occur to a simple alkene while it and the nucleophile are both bound to the palladium atom. Such reactions are known for aryl halides. Even ethylene itself does satisfactory Heck reactions and its reaction with the bromopyridine 132 is the basis for a large scale process leading to a drug.21... 

High yields (90 and 86%) of 2-chloro- and 2-bromo-pyridine are obtained by low-temperature (0—5 °C) halogenation of a palladium(ii) chloride complex of pyridine 2-chloropyridine is converted into 2-bromopyridine by its reaction with gaseous hydrogen bromide. A quantitative conversion of 2-chloro- into 2-methyl-pyridine is achieved by its reaction with methylmagnesium bromide in the presence of a catalyst, readily prepared from 2-chloropyridine and... 

Examples of the formylation of aryl halides with synthesis gas catalyzed by palladium complexes are summarized in Equation 19.90. These reactions relied upon the development of ligands with particular steric and electronic properties. The dia-damantyl-n-butyl phosphine shown in the equation, in combination with palladium acetate, leads to the formation of aromatic aldehydes in high yields from electron-rich and electron-poor aryl bromides. Reactions of nitroarenes and 2-bromopyridine provided the aldehydes in low yield, but other examples occurred in satisfactor) yield with only 0.1-0.75 mol % catalyst. The identity of the base is important in this process, and TMEDA was the most effective base. The mechanism of this process was not proposed in the initial work, but is likely to occur by oxidative addition of the aryl halide, insertion of the carbon monoxide into the palladium-aryl bond, and a combination of hydrogenolysis of the acyl intermediate and elimination of hydrogen halide to regenerate palladium(O). The base would then be involved in the hydrogenol5 sis and consumption of hydrogen halide. 

The intermolecular Heck reaction of halopyridines provides an alternative route to functionalized pyridines, circumventing the functional group compatibility problems encountered in other methods. 3-Bromopyridine has often been used as a substrate for the Heck reaction [124-126]. For example, ketone 155 was obtained from the Heck reaction of 3-bromo-2-methoxy-5-chloropyridine (153) with allylic alcohol 154 [125]. The mechanism for such a synthetically useful coupling warrants additional comments oxidative addition of 3-bromopyridine 153 to Pd(0) proceeds as usual to give the palladium intermediate 156. Subsequent insertion of allylic alcohol 154 to 156 gives intermediate 157. Reductive elimination of 157 gives enol 158, which then isomerizes to afford ketone 155 as the ultimate product This tactic is frequently used in the synthesis of ketones from allylic alcohols. 

Trialkylstannyl groups can also be replaced by reactive electrophiles in certain cases, but most commonly stannylated azaheterocycles are employed in palladium catalyzed cross-coupling reactions [85PAC1771 86AG(E)508 92S413]. For example, trimethylstannylpyridines can be reacted with bromopyridines in the presence of catalytic amounts of tetrakis-(triphenylphosphine)palladium to give a variety of different bipyridines (Scheme 158)(86S564). 

Acetylene can be made to react with aryl iodides in the presence of [PdCl2(PPh3)2] and Cul as catalyst (equation 180) 631 The potential intermediate, phenylacetylene, was not observed. (E) - 2-Bromostyrene and 2-bromopyridine also underwent the reaction. The initial reduction of palladium(II) to palladium(O) is believed to involve the coupling of two moles of acetylene. The precise mechanism is not known, but the reaction is thought to proceed according to Scheme 68. 

A procedure has been developed for the palladium-catalysed a-arylation of amides by aryl bromides using the zinc enolates of the amides. The reaction works well with bromoarenes carrying a variety of ring substituents and with bromopyridine. In addition, the reaction has been shown to be effective with morpholine amides to give products which are precursors for aldehydes and ketones.39 A new method has been reported for the allylation of aryl halides using homoallyl alcohols as the allyl source the palladium-catalysed reaction, which may be both stereo- and regio-sepecific, uses a retro-allylation reaction to form a a-allyl(aryl)palladium intermediate.40... 

The palladium-catalyzed, microwave-assisted conversion of 3-bromopyridine to 3-cyanopyridine using zinc cyanide in dimethylformamide (DMF) has been reported <2000JOC7984>. Substoichiometric quantities of copper or zinc species improve both conversion rate and efficiency of Pd-catalyzed cyanation reactions <1998JOC8224>. A modification of this procedure uses a heterogeneous catalyst prepared from a polymer-supported triphenylphosphine resin and Pd(OAc)2 the nitriles were obtained from halopyridines in high yields <2004TL8895>. The successful cyanation of 3-chloropyridine is observed with potassium cyanide in the presence of palladium catalysts and tetramethylethylenediamine (TMEDA) as a co-catalyst <2001TL6707>. 

Diaryl ketones can also be prepared by coupling aryl iodides with phenylboronic acid (12-28), in the presence of CO and a palladium catalyst.This reaction has been extended to heteroaromatic systems, with the preparation of phenyl 4-pyridyl ketone from phenylboronic acid and 4-iodopyridine. 2-Bromopyridine as coupled with phenylboronic acid, CO and a palladium catalyst to give phenyl... 

Suzuki coupling reaction of phenylboronic acids such as 74 with 4-bromopyridine [34]. Inada and Miyuara [35] have extended the method to 2-chloroquinoline 25. Therefore, the coupling between 25 and phenylboronic acid 74 led to 2-tolylquinoline 75 in 91% yield. The catalyst was recovered with ease and used in further coupling reactions. Not surprisingly, the couplings of phenylboronic acids with electron-rich chloroarenes were ineffective due to their slow oxidative addition to the palladium(O) complex. This reaction is an example where even quinolinyl chloride is a good substrate for the oxidative addition of Pd(0) if the chlorine atom is at the activated position (a or 8). 

---