Amination reactions aminopalladation

Intramolecular aminopalladation has been applied to the total synthesis of the complex skeleton of bukittinggine (179). For this reaction. Pd(CF3CO )2 (10 mol%) and benzoquinone (1.1 equiv.) are used. It is important to use freshly recrystallized benzoquinone for successful cyclization. Formation of a 7r-allylpalladium species as an intermediate in this amination reaction has been suggested 182]. The amino group in obromoaniline reacts first with acrylate in the presence of PdCF to give 180, and then intramolecular Heck reaction of the resulting alkene 180 with Pd(0) catalyst affords indolecarboxylate 181[183]. 

In recent years, there has been a considerable focus on the development of new reaction conditions that use only molecular oxygen as the co-oxidant and do not require DMSO solvent [19]. Considerable progress has been made through the use of palladium catalysts supported by pyridine or N-heterocyclic carbenes as ligands. For example, Stahl has demonstrated that the 2-allylaniline derivative 14 is transformed to indoline 15 in 79% yield upon treatment with 5 mol% IMesPd(TFA)2 and 10 mol% benzoic acid (Eq. (1.8)) 19d]. Stoltz has reported the conversion ofamide 16 to lactam 17 under similar reaction conditions (Eq. (1.9)) [19b]. Through elegant mechanistic studies Stahl has shown that the stereochemistry of the aminopalladation step is dependent on reaction conditions, and both syn- and antt-aminopalladation mechanistic pathways are accessible in oxidative amination reactions [20]. 

A related approach to the synthesis of nitrogen heterocycles also proceeds via Pd -catalyzed alkene aminopalladation, but involves substrates bearing allyhc acetates or allylic hydroxy groups [21, 22]. In contrast to the oxidative amination reactions described above, these transformations are terminated by 3-elimination of the acetate or hydroxy group (rather than P-hydride elimination). This approach alleviates the need for added oxidants, but does require the use of slightly more complex substrates. Nonetheless, this method is quite useful, and has been applied to the synthesis of... 

Unlike the intermolecular reaction, the intramolecular aminopalladation proceeds more easily[13,14,166], Methylindole (164) is obtained by the intramolecular exo amination of 2-allylaniline (163). If there is another olefinic bond in the same molecule, the aminopalladation product 165 undergoes intramolecular alkene insertion to give the tricyclic compound 166[178]. 2,2-Dimethyl-l,2-dihydroquinoline (168) is obtained by endo cyclization of 2-(3,3-dimethyiallyl)aniline (167). The oxidative amination proceeds smoothly... 

The stereochemistry of the aminopalladation reaction with (E)- and (Z)-2-butene was initially established by a three-step conversion of the unstable er-complexes, obtained by the addition of a secondary amine, to 2-butenes11. However, direct proof was obtained by the addition of excess dimethylamine to the same er-complexes the corresponding azapalladacy-clobutanes so formed at low temperature were analyzed by 13C-NMR spectroscopy, which allowed the relative stereochemistry to be assigned12. 

Various heterocychc compounds can be synthesized by Pd(II)-catalyzed reaction of alkynoic alcohols, carboxylic acids and amines via oxy- or aminopalladation... 

Formation of the pyrrole 278 from l-amino-3-alkyn-2-ol 276 is catalyzed by PdCl2. The reaction can be understood as aminopalladation to generate 277, followed by protonolysis and dehydration [116]. Indoles are prepared from o-alkynyl aromatic amines. The required alkynyl amine 279 is prepared from o-iodoacetanilide. Aminopalladation of 279 and protonolysis affords 280 [117]. 

Pd-catalyzed and promoted reactions of allenes can be classified into three groups. The first one is promoted by Pd(II). For example, aminopalladation of hexa-l,2-dienyl-6-amine with Pd(II) generates the alkenylpalladium intermediate 52, which is converted to functionalized alkene 53 with generation of Pd(0). In order to make the reaction catalytic, Pd(0) has to be oxidized to Pd(II) with some oxidants. This type of reaction is treated in Chapter 2.5. 

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... 

The Pd(II)-catalyzed amination of alkenes with aliphatic amines does not proceed well. However, nnder controlled conditions such as -50 °C, a stoichiometric reaction of simple alkenes with the amines gives the aminopalladation intermediates in which coordination of the amines to Pd(II) is involved. The aminopalladation adducts undergo varions nniqne reactions as shown in Scheme However, these reactions appear to be synthetically less useful because of the use of a stoichiometric amount of palladium. 

Because intramolecular cyclization, in general, is entropically favorable, intramolecular aminopalladation of alkenes followed by Pd—H elimination appears to proceed well. However, the basicity of the amine again becomes a crucial factor. The first successful reaction of this type was carried out in 1976 by Hegedus et where less basic ary-... 

The oxidative addition reactions to alkenes promoted or catalyzed by PdCl2(CH3CN)2 have been classified based on the nature of the attacking species. Oxygen nucleophiles such as water, alcohols and carboxylic acids undergo oxypalladation, while ammonia, amines and their derivatives are typical nucleophiles for aminopalladation. Carbopalladation with active methylene compounds is also discussed The palladium-catalyzed intramolecular hetero- and carbopalladation of olefins is extensively used as the ring-forming step in the synthesis of a variety of heterocyclic and carbocyclic systems, and representative examples are provided. 

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). ... 

Reactions via Pd(II)-Alkene Complex In 1980, Hegedus et al. reported on the synthesis of indole derivatives via a Pd-catalyzed intramolecular amination of alkenes in the presence of carbon monoxide (Scheme 40.2). This reaction follows the outersphere aminopalladation mechanism. This report can be considered the first example of today s carboamination reaction although the authors did... 

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