Palladium insertion

Palladium insertion into the phenyl ring of 3-(4-methoxyphenyl)sydnone by lithiation of compound 103, phosphi-nation at C4, then insertion of palladium at the ortho C-H bond to give product 17 has been achieved (Scheme 4)... 

Free-radical cyclization reactions nicely complement the Pd(0)-catalyzed intramolecular Heck reaction, which also provides cyclic products from unsaturated halides. Free radicals can be generated easily at saturated carbons from saturated alkyl bromides, and the products are reduced relative to the reactants. In contrast, intramolecular Heck reactions work best for vinyl and aryl bromides (in fact they do not work for alkyl halides), and the products are at the same oxidation level as the reactants. Moreover, free radicals attack the double bond at the internal position, whereas palladium insertion causes cyclization to occur at the external carbon. 

To determine the mechanism of the above reaction, a modified palladium catalyst, namely Me2Pd(DMPE) 346 (DMPE = l,2-bis(dimethylphosphino)ethane), was reacted with stannylborane 345 and it was observed that the catalysis is triggered by the oxidative insertion of the B-Sn bond across the palladium atom, which was evident by the formation of SnMe4 as well as 5-methyldiazaborolidine 349 along with the expected palladium insertion product 347 (Equation 17) <1996OM5450>. 

As shown in Equation (37), 4,5-dibromo-2-furaldehyde and methyl 4,5-dibromo-2-furoate underwent regioselective cross-coupling reaction at the 5-position with alkynes under Sonogashira-type conditions, presumably due to the activation of the 5-position by the electron-withdrawing groups at the 2-position toward oxidative palladium insertion <1998TL1729, 1999EJO2045>. 

In general, the process is easy for coordinatively unsaturated metal species, in particular 16-electron (d and d ) metals [Ni(0), Pd(0)], since these can attain a stable 18-electron configuration as a consequence. Additionally, two metal oxidation states must be sufficiently stable. For example, tetrakis(triphenylphosphine)palladium inserts readily at 80 °C into the C-Br bond of bromobenzene to give the organometallic complex PhPd(PPh3)4Br. 

Bromoquinolines behave in the Suzuki reaction similarly to simple carbocyclic aryl bromides and the reaction is straightforward. Examples include 3-(3-pyridyl)-quinoline 80 from 3-bromoquinoline 58 and 3-pyridylboronic acid 79 [36] and 3-phenyl-quinoline 83 from substituted 3,7-dibromoquinoline 81 and (2-pivaloylaniinophenyl)boronic acid 82 [37]. Notice that the combination of potassium carbonate and ethanol resulted in debromination at the C(7) position (but the combination of sodium carbonate and methanol left the C(7) bromide intact). It was speculated that the debromination arose from a second palladium insertion, followed by hydrolysis of the intermediate. Further manipulations of biaryl 83 delivered an interesting ll//-indolo[3,2-c]quinoline 84. The result is particularly intriguing since the cyclization of the azide is regioselective which is not usually the case in the pyridine series [38]. 

The next section will switch from classic oxidation processes to formal oxidation state changes at the carbon center. These types of processes parallel nonoxidative cross-coupling processes however, in these examples the carbon atom is fully reduced and a directing group is typically employed to guide the C-H palladium insertion event. Thus after reductive elimination the carbon atom has been formally oxidized/functionalized. 

As with other transition metal-catalyzed reactions (Ziegler-Natta polymerization of alkenes, olefin metathesis), the mechanism of the Heck reaction is complicated. In brief, the species that reacts with the aryl halide is I Pd, where L is a ligand such as tiiphenylphosphine. By a process known as oxidative addition, palladium inserts into the carbon-halogen bond of the aryl halide. 

The pyrazin-2-ylidene 88 was formed by decarboxylation of its pseudocross-conjugated precursor by decarboxylation (20130L4806). Results of mass spectrometric examinations are available (1999MI925). Palladium insertions into chloropyridazine and phthalazine, respectively, resulted in the formation of the phthalazine derivatives of 89 (2012OM8537), i.e., phthalazinylidenes (1990JCS(P)555). 

Amines and alcohols are oxidized to the corresponding imine (or iminium ion) and carbonyl compounds, respectively, with palladium catalysts. Coordination of heteroatom to palladium, insertion of palladium into hydrogen-heteroatom bonds, and /3-elimination of palladium hydride species are involved in these reactions. 

Aluminum Reagents. Alanes are effective donors of an alkyl group to Pd(II) after the palladium insertion into a carbon-halogen or a carbon-oxygen bond. All carbon positions in pyrazine are electrophilic. Therefore, chloropyrazines can be used as substrates for the methylation with trimethylalanes as in the preparation of the methylpyrazine A-oxides 250 and 251 (Scheme Triflated 5-hydroxy-l,3-... 

The complex catalytic cycle commences with oxidative palladium insertion on the aryl iodide bond. The following carbopalladation with norbornene creates a bulky intermediate that is not prone to p-hydride elimination and allows C-H activation of the ortho position of the aryl moiety. Subsequent oxidative addition of the alkyl iodide allows cross-coupling and elimination of the norbornene by retro-carbopalladation. The remaining intermediate 146 then undergoes aMizoroki-Heck reaction with the acrylate, which completes the catalytic process and furnishes the desired cinnamate 148 derivative. 

A different strategy and very elegant approach combines the palladium insertion into an aryl halide, subsequent Heck reaction, and an intramolecular arylation through C—H activation. In 2004, Larock published the synthesis of various polycycles by utilizing such a tandem protocol [131]. The sequence leading to tetracycle 217 is shown in Equation 12.40-1, Scheme 12.40. The sequential palladium-catalyzed reactions allow the efficient elaboration of complex polycyclic frameworks, which are commonly observed in natural products. 

Buchwald has attempted to intercept the same sulfinate using a palladium catalysed boronic acid coupling (Scheme 18.3). Instead, of the palladium inserting into the S-Cl bond as was expected, Buchwald found that the Pd inserted into the S-OPh bond leading to the generation of the sulfonyl chloride. 

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