Aminopalladation reductive elimination reactions

Battistuzzi G, Cacchi S, Fabrizi G (2002) The aminopalladation/reductive elimination domino reaction in the construction of functionalized indole rings. Eur J Org Chem 2671-2681... 

V.3.3.2 Aminopalladation-Reductive Elimination Domino Reactions with Organopalladium Derivatives... 

The nucleophilic strength of the nitrogen, the substitution pattern of the alkyne, the absence or the presence—as well as the nature—of phosphine ligands, the solvents, the added salts, and even the ratios between them are among the main factors influencing the conrse of the aminopalladation-reductive elimination domino reaction. 

Extension of the aminopalladation-reductive elimination domino methodology to the conunercially available ethyl iodoacetate provides a new approach to the construction of indole rings containing the 3-(ethoxycarbonyl)methyl group. Employment of the same conditions reported for the preparation of 2,3-disubstituted indolesf and 2-unsubstituted 3-arylindoles fail to give the desired indole derivatives, at least with the model system, the Af-alkyl derivative being the main or sole reaction product (Scheme 22). 

The aminopalladation-reductive elimination domino reaction of alkynes containing nitrogen nucleophiles close to the carbon-carbon triple bond has been shown to be a valuable methodology for the synthesis of the pharmaceutically important indole ring system and a variety of nitrogen-containing heterocycles. 

The fate of this Tj -alkyne-organopalladium intermediate has been found to depend on a number of reaction variables. For example, in the presence of a nucleophile close to the carbon-carbon triple bond, it can enter the carbopalladation- - oxypaUadation,- " or aminopalladation- reductive elimination domino reaction path or, when the reaction is carried out with a terminal alkyne, it can produce coupling products. ... 

The 2-substituted 3-acylindoles 579 are prepared by carbonylative cycliza-tion of the 2-alkynyltrifluoroacetanilides 576 with aryl halides or alkenyl tri-flates. The reaction can be understood by the aminopalladation of the alkyne with the acylpalladium intermediate as shown by 577 to generate 578, followed by reductive elimination to give 579[425]. 

One of the most common methods employed for the generation of allylpalladium complexes involves oxidative addition of allylic electrophiles to Pd . This transformation has been explored by several groups, and has been the topic of recent reviews [69]. A representative example of this process was demonstrated in a recent total synthesis of (+ )-Biotin [70]. The key step in the synthesis was an intramolecular amination of 89, which provided bicydic urea derivative 90 in 77% yield (Eq. (1.40)). In contrast to the Pd"-catalyzed reactions of allylic acetates bearing pendant amines described above (Eq. (1.10)), which proceed via alkene aminopalladation, Pd -catalyzed reactions of these substrates occur via initial oxidative addition of the allylic acetate to provide an intermediate Jt-allylpalladium complex (e.g., 91). This intermediate is then captured by the pendant nudeophile (e.g., 91 to 90) in a formal reductive elimination process to generate the product and regenerate the Pd catalyst. Both the oxidative addition and the reductive elimination steps occur with inversion... 

A somewhat different approach was pursued by Sanford, who made use of an intermolecular aminopalladation with phthalimide as nitrogen source (Scheme 4.9) [33]. Again, this reaction follows the syn-addition pathway of Stahl and, after coordination of the alcohol from the substrate and upon oxidation of the palladium intermediate, a six-membered ring chelate at palladium] IV) E was suggested. This compound undergoes direct syn-reductive elimination to arrive at the observed overall stereochemistry for the THF product. For chiral homoallylic substrates, the initial aminopalladation proceeds with anti-diastereoselectivity. Such substrate-directing behavior had already been discussed by Stahl in his aminopalladation reactions [30]. 

In 2010, Jaegli et al. reported a novel palladium-catalyzed intramolecular domino spirocyclization process for the preparation of biologically relevant spiropyrroUdine-3,3 -oxindoles 86 [32] (Scheme 6.19). Oxidative addition of the aryl halide to Pd(0) aminopalladation via the coordinated intermediate 84 leads to palladacycle 85 reductive elimination of complex 85 generates the final product. Both Heck reaction and aminopalladation processes were viable pathways from amide 83, and the route that occurs is dependent on the ligand chosen. The use of tBuMePhos as the ligand is required for the successful formation of spirooxindoles. 

Carboamination reactions have been classified into two types depending on the mode of reaction in the first case, the reaction proceeds via the formation of 1) an outersphere aminopalladation complex like the PdX2-aIkene complex via oxidative addition, which in the next step reacts with the amine and an external electrophile to afford the cyclized product. In a type II mechanism, the reaction takes place through the formation of 2) an innersphere complex where the Pd(0) catalyst forms the complex with an electrophile, e.g., aryl haUde via oxidative addition. Then, it reacts with the amine to form the Pd(Ar) amide complex, which eventually gets converted into the product via the alkene insertion and C—C bond-forming reductive elimination. Here, it is noteworthy that, in a type I reaction, the addition across the olefinic bond took place in rarri-fashion, whereas the 5y -addition mode was observed in case of the type It mechanism (Scheme 40.1). ... 

Experimental evidence for insertion of alkenes into the metal-nitrogen bond was reported recently in the studies of aminopalladation reactions [41,42]. Intramolecular insertion reaction was confirmed to be a yn-addition process and was monitored by NMR spectroscopy of the well-defined palladium(aryl)(amido) complexes (Scheme 11) [41, 43]. The reaction proceeded as insertion into Pd-N bond with complete chemoselectivity and the alternative route of alkene insertion into the Pd-C bond was not observed. The activation enthalpy determined for the insertion step A// = 24.8 zb 0.6 kcal/mol was comparable with the values reported for other insertion reactions, and small activation entropy = 4.6 zb 1.8 eu is consistent with intramolecular transformation [41, 43]. The final product of the reaction was formed after C-C reductive elimination, which is known to be rather fast step if at least one aryl group is involved [44, 45]. The mechanistic study of the alkene insertion into the Pd-N bond has also pointed out on possible reversible nature of such process [46]. 

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