Palladium-catalysed reactions 1,4-elimination

The palladium-catalysed addition of aryl, vinyl, or substituted vinyl groups to organic halides or triflates, the Heck reaction, is one of the most synthetically useful palladium-catalysed reactions. The method is very efficient, and carries out a transformation that is difficult by more traditional techniques. The mechanism involves the oxidative addition of the halide, insertion of the olefin, and elimination of the product by a p-hydride elimination process. A base then regenerates the palladi-um(0) catalyst. The whole process is a catalytic cycle. 

Now the alkene must be moved yet one more time around the ring to prepare the way for another intramolecular Heck reaction. Hydroboration (chapter 17) of 153 is regioselective because of the large N-Boc group and Swem oxidation completes the insertion of the ketone 155. Reduction and elimination use another palladium-catalysed reaction. Conversion to the triflate 157 is followed by Pd-catalysed transfer hydrogenation, the H atom coming from formic acid HC02H. 

When a syn P-hydrogen is present in an alkylpalladium species, a rapid elimination of a palladium hydride occurs, generating an alkene. This reaction is much faster in RPdX than in R2Pd and is the reason that attempted palladium-catalysed reactions of alkyl halides often fail. 

These palladium-catalysed reactions involve insertion of the palladium into the carbon-bromine or carbon-triflate bond, reaction with the organometallic species (alkenyl stannane in a Stille reaction, arylboronic acid in a Suzuki reaction, or alkynyl copper species in a Sonogashira reaction) and reductive elimination to give the products shown below. 

The use of transition-metal catalysts in the substitution of aryl halides by amines has been reviewed. There has also been a summary of the use of palladium catalysts in the reaction of aryl and heteroaryl halides with primary and secondary amines. It has been shown that the amination of aryl sulfamates by aliphatic amines may be achieved using a nickel catalyst with an A-heterocyclic carbene ligand. Suitable ligands for nickel and palladium in the catalysed amination reactions of aryl sulfamates and imidazolylsulfonates have been identified. " The palladium-catalysed reaction of aryl nonafluorobutanesulfonates with primary sulfonamides may yield substituted products such as (22). Kinetic data suggest that reductive elimination from the palladium intermediate is likely to be rate limiting. A-Arylmethanesulfonamides may also be formed from aryl bromides and chlorides using a palladium catalyst... 

The acylation of arenes with alcohols has been shown to be possible using a palladium chloride catalyst in the presence of f-butylhydroperoxide. In 2-arylpyridines, substitution is directed to the ortho-position and, after initial paUadation, the formation of intermediate (59) is likely before reductive elimination yields the acylated product. The regioselective acetoxylation of indoles, at the 3-position, has been achieved using the palladium-catalysed reaction with phenyliodonium acetate. 3-Acyl indoles may also be prepared using acetyl chlorides with zirconium tetrachloride as a Lewis acid catalyst. 

The coupling of anilines with arylboronic acids has been described in a process catalysed by palladium acetate without the need for ligands, bases, or salts. The mechanism shown in Scheme 17, where S represents solvent, involves in situ formation of the dia-zonium salt from the aniline, and formation of an arylpalladium alkoxo complex which allows the transmetallation step with arylboronic acids. It has been shown that a free amine may be used as a DG in a palladium-catalysed reaction promoted by soluble silver salts. The latter aid the formation of intermediates, (136), which may undergo cyclopalladation followed by transmetallation with an arylboronic acid and reductive elimination. Related work has shown thatbiaryl-2-amines may react with aryl iodides in the presence of palladium acetate and silver acetate to give mono- or di-arylated species such as (137). 

In the palladium-catalysed carbonylation of aryl bromides to yield benzaldehyde derivatives, IV-formylsaccharin is used as the source of the acyl function. A double carbonylation has been observed in the reaction of aryl halides with carbon monoxide and terminal alkenes which yields 4-arylfuranones such as (152). The proposed mechanism involves oxidative addition of the aryl halide to palladium and insertion of the carbon monoxide to give an acyl palladium species. This is followed by coordination and insertion of the alkene. A second carbon monoxide insertion is faster than -hydride elimination and, after intramolecular attack, leads to the product. The palladium-catalysed reaction of aryl iodides with simple ketones such as acetone in the presence of carbon monoxide has been shown to yield 1,3-diketones such as... 

Several carbon-hydrogen bond substitutions are involved in the palladium-catalysed reaction of arylsulfonic acids with arenes to yield aromatic sulfones. A plausible mechanism, shown in Scheme 9, involves the initial formation of the palladacycle (99) which, after eoupling with the arene, yields the biphenyl derivative (100). Further coordination and carbon-hydrogen activation gives the seven-membered palladacycle (101) that affords the sulfone, (102), after reductive elimination. ... 

Coordination of palladium with the adjacent pyridine ring is likely to facilitate the acylation of 2-arylpyridines with ct-diketones. In the presence of t-butyl hydroperoxide (TBHP), cleavage of the diketones yields radicals that may allow the formation of intermediates such as (115), which yield the acylated products after reductive elimination. Interestingly the ortfto-aroylation of 2-aryl pyridines may also be achieved using the palladium-catalysed reaction with toluene in the presence of TBHP. Here the mechanism is likely to involve initial benzylation followed by oxidation at the benzylic position to give the acylated product. Acetanilides may also be acylated at the ort/jo-position using toluene and TBHP to yield products such as (116). Here a possible mechanism involves initial formation of a cyclopalladated intermediate followed by reaction with an acyl radical formed by oxidation of the toluene. ... 

The palladium-catalysed reaction of the pyrazolo-pyrimidine derivative (141) with 3-bromotoluene may result in arylation at the 3-position in the pyrazole ring or at an sp hybridized site in the 7-methyl side-chain depending on the base and ligands used. After initial insertion of the palladium catalyst into the aryl halide bond, palladation of (141) occurs by a concerted metalation-deprotonation pathway and is followed by reductive elimination. Concerted metalation-deprotonation is also likely in the palladium-acetate-catalysed reaction of imidazo[l,2-a]pyridines with aryl bromides to give 3-substituted derivatives such as (142). A careful mechanistic study of the arylation of pyridine A-oxide by bromotoluene, catalysed by palladium acetate and t-butylphosphine, has shown that direct reactions of an aryl palladium complex with... 

Indoles with carbocyclic halogen or triflate substituents are potential starting materials for vinylation, arylation and acylation via palladium-catalysed pro-cesses[l]. Indolylstannanes. indolylzinc halides and indolylboronic acids are also potential reactants. The principal type of substitution which is excluded from such coupling reactions is alkylation, since saturated alkyl groups tend to give elimination products in Pd-catalysed processes. 

Not only acetylene derivatives do undergo palladium catalysed intarmolecular carbon-nitrogen bond formation with amines. The similar reaction of olefins in a Wacker-type process also leads to ring closure. (0-Aminopentenes bearing a suitable leaving group in the 4-position were converted to pyrroles in a cyclization-isomerisation-elimination sequence (3.65.),82... 

The rate of the palladium-catalysed Heck-type phenylation of allylic alcohols has been found to be markedly enhanced by addition of tertiary amines454. Regioselectivity can be increased, in some cases, by adding E NCl or employing a Wilkinson Rh catalyst (rather than pd)455 456. Another Heck-type reaction involves addition of arenediazonium tetraflu-oroborates to a-silylstyrenes to give (Z )-PhCH=CHAr. A BF4 -mediated vyw-elimination of silicon and palladium has been suggested to account for the stereochemistry457. 

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