Aminopalladation derivatives

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. 

The transformation (190 — 191) exemplifies the use of transition metal reagents the reaction probably involves aminopalladation of the C = C bond (77JOC1329). 2,3-Dihydro-4(l//)isoquinolones are obtained by Dieckmann cyclization of 7V-(o-alkoxycarbonylbenzyl)glycine ester derivatives (192 - 193). 

Vinyl-substituted 2-oxazolidinones 208 were synthesised by a catalytic <02JOC974> and also asymmetric intramolecular aminopalladation of readily available derivatives of (Z)-2-buten-l,4-diol 207 <02JA12>. 

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). 

Aminocarbonylation of A -4-pentenyl-A -methylurea (146) gave 147 smoothly in the presence of PdCl2, CuCl2 and O2 [61]. Aminocarbonylation of the unsaturated diamine derivative 148 is chemoselective. In the presence of sodium acetate and methyl orthoformate, aminopalladation of the tosylamide took place selectively to Erfford 150 via 149. On the other hand, selective reaction of the carbamate occurred to give 151 in the absence of sodium acetate [62],... 

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]... 

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]. 

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. 

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... 

This same two-step diamination process was employed in the palladiuminternal alkenes (Scheme 4.11) [35]. Here, 2,2 -diamino stilbene derivatives were converted into the corresponding diamines with complete diaster-eoselectivity (Eq. (4.25)). This stereochemical outcome was rationalized by the assumption of an initial amide-palladium interaction, which is unproductive regarding a possible syn-aminopalladation as it would generate an azetidine intermediate. Instead, trans-aminopalladation takes place, followed by rapid oxidation to an q -coordinated benzylic palladium(IV) with preservation of the relative stereochemistry. Anti-C-N-bond formation then displaces palladium(II) to close the catalytic cycle and to displace the C2-symmetric diamine product. 

An alternative approach by Gotthch consists in the isomerization of N-chloro amines 119, which insert a paUadium(O) catalyst and, upon subsequent aminopalladation followed by carbon-chlorine bond installation, give the aminochlorinated product 120, which through an aziridinium intermediate rearranges to the final piperidine derivative 121 (Scheme 16.29) [84]. 

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

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 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. 

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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