Palladacycle Formation

The teleocidin B4 core 15 is synthesized from the Shiff base of 2-/< //-butyl-5-methoxyaniline, as shown in Scheme 16.161 The key sequence of this synthesis consists of two G-H bond functionalizations, alkenylation and oxidative carbonylation of two methyl groups, via palladacycle formations. 

Another example of transient formation of a palladacycle is the Pd-mediated ortho-alkylation and ipso-vinylation of aryl iodides depicted in Scheme 8.23. In this multicomponent reaction the ability of norbomene to undergo reversible arylation and palladacycle formation is exploited. This reaction also illustrates that aryl halides undergo oxidative addition to Pd faster than do alkyl halides, and that aryl-alkyl bond-formation by reductive elimination also proceeds faster than alkyl-alkyl bond-formation. The large excess of alkyl iodide used in these reactions prevents the formation of biaryls. Benzocyclobutenes can also be formed in this reaction, in particular when the alkyl group on the aryl iodide is sterically demanding or when a secondary alkyl iodide is used [161]. 

Scheme 1. Palladacycle formation through a sequence of oxidative addition, insertion, and electrophilic aromatic substitution. L= phosphorous or nitrogen ligands, solvent, or coordinating species.

Scheme 4 Palladacycle formation via electrophilic aromatic substitution...

Once palladacycle formation has occurred, a number of possibilities exist for its reaction. A side product often seen in Catellani reactions is cyclobutane (21) formation resulting from a reductive elimination of the palladacycle (Scheme 7). In fact, under optimized conditions it is possible to achieve good yields of the cyclobutane products [26], However, the focus of this section will be to examine the reaction of the palladacycle with alkyl and aryl halides. 

In the case of the ortho alkylation chemistry, if no pre-existing ortho substituent is present, the species formed after sp3-sp2 coupling resembles complex 4 and, through rotation of the norbornylpalladium(II) group, the other ortho position can be alkylated, again through palladacycle formation. In the case of the ortho... 

A study was carried out to get insight into the reaction of the ring-forming process. Palladacycle formation was found to be faster with para (with respect to the Pd-C bond) electron-releasing substituents than with the electron-with-drawing ones [22]. The process thus corresponds to an electrophilic aromatic substitution (Eq. 12). 

The following compounds with H-C and H-M bonds vmdergo oxidative addition to form Pd hydrides. Reactions of terminal alkynes and aldehydes are known to start by the oxidative addition of their C-H bonds. The reaction, called "ortho-palladation , occurs on the aromatic C—H bond in 3 at an ortho position of such donor atoms as N, S, O and P to form a Pd—H bond and palladacycles. Formation of aromatic palladacycles is key in the C—H bond activation in a number of Pd-catalyzed reactions of aromatic compounds. Some reactions of carboxylic acids and active methylene compounds are desaibed as starting by oxidative addition of their acidic O—H and C—H bonds. 

The key step is the selective C—H bond activation of two methyl groups of an ortho-tert-hutyl in the Schiff base 434. Treatment of 434 with Pd(OAc)2 afforded the palladacycle 435 in 75 % yield by the help of rather strong coordination to N and O functions. The first functionalization was achieved by the reaction with the alkenylboronic acid to yield the alkylated product 436 in 86 % yield, which was converted to 437 by the Friedel-Crafts reaction. Then the second palladacycle formation from 437 provided two diastereomers 438, which were, without isolation, subjected to carbonylation (40 atm) at room temperature. Treatment of crude reaction mixture with silica gel cleaved the Schiff base and spontaneous lactonization occurred to give a mixture of the lactones 439 and 440 (6 1). The main product was N-alkylated to yield 441. Finally, the fourth ring was constructed by a Heck-type reaction on the aromatic ring to give the desired compound. 

Cyclopalladation of (5)-4-fcrf-Butyl-2-methyl-2-oxazoline An Unprecedented Case of ( sp )C-H Bond Activation Resulting in Ero-Palladacycle Formation... 

Fig. 39 a-Alkenyl endo-palladacycle formation via regiospecific activation of a C(sp )-H... 

The Suzuki-Miyaura synthesis is one of the most commonly used methods for the formation of carbon-to-carbon bonds [7]. As a palladium catalyst typically tetrakis(triphenylphosphine)palladium(0) has been used, giving yields of44—78%. Recently, Suzuki coupling between aryl halides and phenylboronic acid with efficient catalysis by palladacycles was reported to give yields of 83%. 

The use of well-defined complexes has been widespread in this reaction, despite intriguing studies by Beller and others that have shown that in situ catalytic systems often give better yields in comparison to isolated carbene-Pd(O) complexes [147-149]. Since the mechanism consists of an oxidative addition on a Pd(0)-monocarbene species, efforts in catalyst synthesis have been directed towards Pd(ll)-monocarbene complexes with other labile groups that can be easily released leading to the formation of Pd(0). This is the case for dimers of the type [Pd( j,-C1)C1(NHC)]2, a family of pre-catalysts effective under aerobic conditions [150], the [Pd(acac)Cl(NHC)] complexes [151] and related palladacycles [152-154],... 

We have shown that the direct arylation of acrolein toward the synthesis of cinnamaldehyde derivatives was an efficient procedure. Using the palladacycle 1 as catalyst, substituted aldehydes 3 were prepared with up to 87% isolated yield from condensed aiyl bromides (Scheme 21.1, Route 1) that was extended successfully to heteroaiyl bromides, like bromoquinolines (6). Alternatively, the acrolein diethyl acetal was used as olefin and a selective formation of the saturated ester 4 was attained under the same reaction conditions (Scheme 21.1, Route 2). The expected aldehydes 3 were, however, obtained from most of the aiyl halides used under modified conditions. It was shown that the addition of n-Bu4NOAc in the medium... 

This process is likely to proceed via a palladacycle intermediate followed by a Pd(ll) to Pd(iv) oxidation. Reductive elimination occurs with C-O bond formation and regeneration of the Pd(ll) catalyst. Evidence for a palladacycle intermediate is supported by the high regioselectivity (8-Me group oxidized) observed for the oxidative functionalization of 5,8-dimethylquinoline, which, in the absence of a possibility of coordination, would otherwise contain two identical methyl groups (Equation (57)). 

Related, earlier examples involve the formation of palladacycle intermediates (Equations (154) and (155)). 

A mechanism involving a palladacycle E has been proposed to explain the formation of such a crossover product (Scheme 28).131... 

A catalytic variant of this process exists, enabling C-C bond formation involving palladacyclic intermediates (Equation (201)).163... 

Intramolecular arylation of G-H bonds gives cyclic aromatic compounds. In this intramolecular arylation, the carbon-palladium cr-bond is first formed by the oxidative addition of Pd(0) species and then the resulting electrophilic Pd(n) species undergoes the intramolecular G-H bond activation leading to the formation of the palladacycle, which finally affords the cyclic aromatic compounds via reductive elimination.87 For example, the fluoroanthene derivative is formed by the palladium-catalyzed reaction of the binaphthyl triflate, as shown in Scheme 8.88 This type of intramolecular arylation is applied to the construction of five- and six-membered carbocyclic and heterocyclic systems.89 89 89 ... 

At high substrate, or low hydrogen concentration, the semihydrogenation of 4-octyne is inhibited by the formation of catalytically inactive palladacycle species. These species are formed by oxidative coupling of two substrate molecules. 

The domino carbonylation and Diels-Alder reaction proceed only as an intramolecular version. Attempted carbonylation and intermolecular Diels-Alder reaction of conjugated 2-yne-4-enyl carbonates 101 in the presence of various alkenes as dienophiles give entirely different carbocyclization products without undergoing the intermolecular Diels-Alder reaction. The 5-alkylidene-2-cyclopenten-4-onecarboxy-lates 102 were obtained unexpectedly by the incorporation of two molecules of CO in 82% yield from 101 at 50 °C under 1 atm [25], The use of bidentate ligands such as DPPP or DPPE is important. The following mechanism of the carbocyclization of 103 has been proposed. The formation of palladacyclopentene 105 from 104 (oxidative cyclization) is proposed as an intermediate of 108. Then CO insertion to the palladacycle 105 generates acylpalladium 106. Subsequent reductive elimination affords the cyclopentenone 107, which isomerizes to the cyclopentenone 108 as the final product. 

In transition metal complexes of suitable geometry the metal may undergo intramolecular oxidative insertion into C-H bonds. Intermediates of Pd-catalyzed C-C bond formation can also undergo such cyclometalations to yield palladacycles . This can give rise to unexpected products or, if the palladacycles are too stable, the catalyst will be consumed and no further reaction will occur. At high temperatures reductive elimination from such complexes can occur to yield cyclic products. 

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