Intramolecular reactions aminopalladation

Oxidative amination of aromatic amines which are less basic than aliphatic amines proceeds smoothly without protection of amines. The intramolecular reaction of aniline derivatives offers good synthetic methods for heterocycles. 2-Methylindole is obtained by 5-exo amination of 2-allylaniline [50]. As an application, A-methyl-2-methyl-3-siloxyindole 114 was prepared from A-methyl-2-(l-siloxyallyl)aniline 113. Without silyl protection, no reaction occurred [51]. If there is another olefinic bond in the same molecule, the aminopalladation product 116 of the amide 115 undergoes olefin insertion to give the tricyclic compound 117 [50]. 2,2-Dimethyl-1,2-dihydroquinoline (119) was obtained by 6-endo cyclization of 2-(3,3-dimethylallyl)aniline (118). 

Intramolecular reaction of allenes is known to proceed mainly by palladation at the central carbon to generate alkenylpalladium 235, which undergoes further reactions. Also TT-allylpalladium 236 is formed when a nucleophile attacks the central carbon. The intramolecular aminopalladation of the 6-aminoallene 237, followed by CO insertion, afforded the unsaturated amino ester 238. The reaction has been applied to the enantioselective synthesis of pumiliotoxin [103]. Oxycarbonylation of the allenyl alcohol 239 afforded the unsaturated ester 240 in 83 % yield using a catalytic amount of PdCl2 and 3 equivalents of CuCb in MeOH and is used for the synthesis of rhopaloic acid [104]. 

The intermediate 190 of the intramolecular aminopalladation of an allenic bond with jV-tosylcarbamate undergoes insertion of allylic chloride. Subsequent elimination of PdCl2 occurs to afford the 1,4-diene system 191. The regeneration of Pd(II) species makes the reaction catalytic without using a reoxidant[190]. 

A Pd(II)-catalyzed sequential cyclization-coupling reaction of allenyl N-tosylcar-bamates and acrolein has been developed (Scheme 16.97) [103]. The proposed mechanism involves intramolecular aminopalladation of an allene, followed by insertion of acrolein and carbon-Pd bond protonolysis. 

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]. 

The usefulness of Pd-catalysed reactions is demonstrated amply in the total synthesis of clavicipitic acid [76]. The first step is intramolecular aminopalladation of the 2-vinyltosylamide 92 with Pd(II) to give the indole 93. Then stepwise Heck reactions of the iodide and bromide of 94 with two different alkenes 95 and 96 in the absence and presence of a phosphine ligand give 97. In the last step of the synthesis, the intramolecular aminopalladation of 97 with a catalytic amount of Pd(II) gives the cyclized product 99. It should be noted that the aminopalladation is a stoichiometric... 

In these reactions, the nitrogen nucleophile is typically an amide, carbamate, or sulfonamide. Because of the low nucleophilicity of such nitrogen functions, no intermolecular 1,4-addition involving C—N bond formation is known. In all cases reported, the carbon-nitrogen coupling takes place in an intramolecular aminopalladation. 

Hegedus proposed that the mechanism of this transformation proceeds through a Wacker-type reaction mechanism that is promoted by Pd(II). As shown below, coordination of the olefin to Pd(II) results in precipitate 121, which upon treatment with Et,N undergoes intramolecular trany-aminopalladation to afford intermediate 122. As expected, the nitrogen atom attack occurs in a 5-exo-trig fashion to afford 123. [l-Hydride elimination of 123 gives rise to exocyclic olefin 124, which rearranges to indole 120. The final step of this mechanism leads to the formation of catalytically inactive Pd(0). However, addition of oxidants such as benzoquinone allows for catalytic turnover. 

Two recent reports have described Pd"-catalyzed carboamination reactions involving two alkenes that afford pyrrolidine products. Building on early work by Oshima that employed stoichiometric amounts of palladium [44], Stahl has developed an inter-molecular Pd-catalyzed coupling of N-allylsulfonamide derivatives with enol ethers or styrene derivatives that affords substituted pyrrolidines in high yields with moderate diastereoselectivity [45]. For example, treatment of 44 with styrene in the presence of Pd" and Cu" co-catalysts, with methyl acrylate added for catalyst stability, provided 45 in 97% yield with 1.9 1 dr (Eq. (1.21)). This reaction proceeds through intermolecular aminopalladation of styrene to afford 46. Intramolecular carbopalla-dation then provides intermediate 47, and subsequent P-hydride elimination yields product 45. 

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... 

Michael recently described aminochlorination reactions from intramolecular aminopalladation follotved by reaction tvith N-chlorosuccinamide (NCS) [17]. Initial reactions made use of Michael s earlier observation on stabilization of aminopallada-tion intermediates starting from 5 mol% ligated Pd complex A [18], but further tvork shotved that simple palladium salts such as Pd(NCMe)2Cl2 could also be employed, albeit in higher catalyst loadings of 10 mol% (Eq. (4.7)). The reaction tvorks well for a series of amides and carbamates, but not for tosylates. 

The stereochemistry of aminopalladation, as is involved in the initial step of the aza-Wacker reaction, is still a subject of ongoing research. A particularly extensive mechanistic study by Stahl and Liu uncovered the stereochemical aspects of intramolecular aminopalladation under Wacker-type conditions. Here, the selectively deuterated compound 46 was used to probe the overall mechanism through product evaluation. It turned out that, for almost all common catalyst combinations, the reaction led to two deuterated alkenes, which were identified as product 47 and its regioisomer. As the final step of 3-hydride elimination must be a syn-selective... 

Additional experiments with the same catalyst source showed further that addition of a base such as sodium acetate or sodium carbonate also promoted the syn-aminopalladation pathway. Obviously, under basic conditions, aminopalla-dation occurs through alkene insertion into a palladium amidato complex with a defined Pd-N bond [45]. Additional experiments by Stahl and White [46] employing an isolated palladium suUbnamidato complex and its intramolecular aminopallada-tion product suggested the alkene insertion reaction to be reversible in nature but to be turned over irreversibly in the presence of molecular dioxygen. Electronically enriched amidates favor the alkene insertion reaction. 

Reactions that are initiated by intramolecular aminopalladation have achieved considerable attention [6d]. This may be, first, due to the fact that this reaction provides access to a series of nitrogen heterocycles, which are important subunits in alkaloids, pharmaceuticals, and other molecules of biological interest Second, the resulting aUcyl-paUadium intermediate may undergo a range of subsequent reactions of further diversification making use of the whole portfolio of palladium-catalyzed reactions. The details on syn- and anti-aminopalladation have already been discussed in connection with Figure 16.1. 

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-... 

In summary, intramolecular aminopalladation, which has been studied extensively, compared to its intermolecular version, is undoubtedly useful for synthesizing N-heterocycles. Control of basicity and nucleophilicity of the N atom is crucial in this type of reaction. Considering such a fundamental feature, efforts will be directed toward the development of an asymmetric version of aminopalladation, which has not been studied much so far. 

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