Aminopalladation synthesis

The Hegedus indole synthesis involves one of the earlier (formal) examples of olefin hydroamination. An ortho-vinyl or ortho-nllyl aniline derivative 1 is treated with palladium(II) to deliver an intermediate resulting from alkene aminopalladation. Subsequent reduction and/or isomerization steps then provide the indoline or indole unit 2, respectively. 

An example of an intramolecular palladium-catalyzed oxidation of an allene involving carbonylation was used in the synthesis of pumilotoxin 251 D (equation 32)65. Intramolecular aminopalladation of the allene followed by carbonylation of the palladium-carbon bond and subsequent oxidative cleavage of the acylpalladium intermediate by CuCE afforded pyrrolidine 72 in which the chirality at the carbon at the 2-position was established. 

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]. 

Cyclization of 8-allenylamines is successful also. Synthesis of 2-alkenylpiperidines can be effected with mercury(II) or silver salts, with silver salts giving higher yields (equation 141 and Table 35).268a The significant asymmetric induction found in the cyclization of a chiral allene (78% ee, entry 2) suggests that the low stereoselectivity observed in the synthesis of the 2,6-disubstituted system (entry 3)269 may be a result of starting with a diastereomeric mixture. Aminopalladation/methoxycarbonylation has been effected in moderate yield also (entry 4). 

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... 

As described in Section 4.1. (Scheme 29), in the frequently reviewed synthesis of N-acetyl ( )-clavicipitic acid methyl ester (167) by Hegedus [80, 81], intramolecular aminopalladation of 164 was accomplished by a Pd(n)-catalyzed process lo give the tricyclic azepinoindole 16S. 

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]. 

Iodo- and o-bromoanilines as well as the corresponding carboxamides and sulfonamides can undergo Pd-catalyzed o-alkenylation and o-alkynylation. The cross-coupling products thus formed can then undergo catalytic aminopalladation to give indole derivatives. A few representative procedures for the synthesis of indoles are shown in Scheme 53.[i45].[i46]... 

An efficient paUadium(II)-catalyzed synthesis of heterocycle-fused P-naphthylamines was accomplished via nucleophilic addition of a carbon-palladium bond to the intramolecular cyano group initiated by nucleopal-ladation (oxypalladation or aminopalladation) ofalkynes (140L6184). 

Synthesis of Saturated Nitrogen Heteroc des via Aikene, Aikyne, or Allene Aminopalladation Reactions... 

A number of approaches to the synthesis of saturated five-membered nitrogen heterocycies involve aikene, aikyne, or allene aminopalladation as a k step [2b,g]. 

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... 

Yang has reported a related tandem cydization for the synthesis of pyrroloindoline derivatives that also proceeds though a mechanism involving alkene aminopalladation followed by carbopalladation of a second alkene [46]. As shown below, the 2-allylaniline derivative 48 was converted to 49 in 95% yield through treatment with a catalyst composed of Pd(OAc)2 and pyridine (Eq. (1.22)). Use of (-)-sparteine as a ligand in this reaction provided 49 with up to 91% ee. 

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 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 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. 

Shi et al. reported a unique indole synthesis from simple anilines without the aid of any directing group on the nitrogen [34]. Thus, aniline itself (85) couples with dimethyl acetylenedicarboxylate (2b) in the presence of Pd(OAc)2 under O2 to produce indole 86 (Scheme 25.41). A reaction mechanism involving initial hydroam-ination/palladation or aminopalladation of 2b and subsequent cyclopalladation has been proposed. 

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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