Pd-catalyzed allylic substitution

The best results were obtained in apolar media using a mixture of dimethyl malonate and, 0-bis(trimethylsilyl)acetamide (BSA), according to a procedure 

Palladium catalysts with aza-semicorrin and bis(oxazoline) ligands have also been successfully applied in analogous reactions of l-aryl-3-alkyl- and 1- 

Palladium(II)-allyl complexes with these ligands were found to be effective catalysts for allylic alkylations with stabilized carbanions. Under standard conditions, using 2 mol% of catalyst and a mixture of BSA and catalytic amounts of KOAc as base, racemic l,3-diphenyl-2-propenyl acetate smoothly reacted with dimethyl malonate or acetylacetone to afford optically active substitution products (Table 1). The phosphinophenyl-oxazoline with a phenyl group at the stereogenic center proved to be the optimal ligand for this substrate. After a remarkably short reaction time, the desired substitution products were isolated in essentially quantitative yields with enantiomeric excess of 97-99%. These values exceed the selectivities previously obtained with other ligands [41-43]. 

At present, no simple mechanistic rationale for the observed enantioselec-tion can be offered. Compared to analogous reactions using C2 Symmetric nitrogen ligands, which may be rationalized in a straightforward manner (see above), the situation here is more complex. With non-symmetric phosphi- 

Further studies, exploring the scope of these catalysts and the mechanism of enantioselection, are in progress. Considering the promising results obtained so far, it will be interesting to test phosphinoaryl-oxazolines as ligands in other metal-catalyzed reactions. 

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Scheme 6 The catalytic cycle for Pd-catalyzed allylic substitution.

In general, Pd-catalyzed allylic substitutions with soft nucleophiles involve nudeophilic attack directly on the allyl unit, on the opposite face to that occupied by the metal. This is contrasted with the situation for hard nucleophiles where the initial attack occurs at the metal, with subsequent migration of the nudeo-phile to the allyl moiety - the addition to the allyl unit therefore occurring from the same face as the metal. Obviously, this has profound implications on the stereochemical outcome. 

Hydroxylamine derivatives are ambident nucleophiles. For example, N-benzylhy-droxylamine functions as an N-nucleophile in the Ir-catalyzed allylic substitution, while N-Boc-hydroxylamine yields mixtures of the N- and O-substituted products in Ir- as well as Pd-catalyzed allylic substitutions. Accordingly, either O- or N,0-protected hydroxylamine derivatives need to be used as nucleophiles [63]. 

Scheme 2 NHC/Pd-catalyzed allylic substitution with dimethyl malonate...

Allylindium reagents can be utilized in the Pd-catalyzed cross-coupling reaction with aryl halides. The Pd-catalyzed allylic substitution of allyl carbonate produces 1,5-dienes (Scheme 103).353-355... 

In this sense Organ and coworkers [80] have developed intriguing syntheses of polysubstituted olefins based upon consecutive intermolecular reactions such as allylic and allylic-vinylic halide coupling sequences. Therefore, l-acetoxy-4-chloro but-2-ene can be readily submitted as a template for Pd-catalyzed allylic substitutions with two different carbon or nitrogen nucleophiles, leading to unsymmetrically substituted butene derivatives 66-70 in good yields (Scheme 22). Mechanistically, the chloro substituent is replaced... 

Vinyl isoxazolidine 84 was prepared by intramolecular 5-exo Pd-catalyzed allylic substitution of hydroxylamine 83. A comparative study on the Pd-based catalytic system proved that Pd(II) in the presence of lithium halides was the most selective catalyst giving the trans isoxazolidine 84 from syn-83 and the czs-84 from the isomeric anti-83 <07SL944>. 

Multinuclear metal complexes that may act as active catalysts or off-cycle species can also be easily identified and studied via ESl-MS. For example, analysis of a simple Pd-catalyzed allylic substitution reaction lead to the discovery of two reversibly formed binuclear bridged palladium complexes (Fig. 6) that act as a reservoir for the active mononuclear catalyst [21], The observation of dimers when using ESl-MS is common and it is crucial to confirm that they truly exist in solution and are not just formed during the ESI process, in this case the detection was supported by P and H NMR studies of stoichiometric reaction mixtures and in situ XAFS experiments [49]. 

The Pd-catalyzed allylic substitution reactions proceed via TT-allyl complex, so that branched and linear substrates yield the same products (Scheme 5.7). 

Pd-catalyzed allylic substitutions such as the Tsuji-Trost reaction have been investigated widely, essentially in their asymmetric version [44]. This represents a valuable tool in organic synthesis since the catalyst can accommodate various functionalities on the substrate and it is possible to tune the coordination sphere through the electronic and steric effects of the ligands. Those which contain a sulfur atom are based on an oxazoline backbone, and an ee as high as 96 % has been... 

Sato, Y., Yoshino, T., Mori, M. Pd-Catalyzed Allylic Substitution Using Nucleophilic N-Heterocyclic Carbene as a Ligand. Org. Lett. 2003, 5, 31-33. 

Problem 6.24. Draw a mechanism for the following Pd-catalyzed allylic substitution reaction. 

The 1,4-conjugate addition of triorganoindium to enones is promoted by a catalytic amount of Ni(COD)2 (Scheme 8.71) [100], Allylindium reagents can be used in Pd-catalyzed cross-coupling reaction with aryl halides (Scheme 8.72). The Pd-catalyzed allylic substitution of allyl carbonate produces 1,5-dienes (Scheme 8.73) [101]. The indium-mediated palladium-catalyzed Ullmann-type reductive coupling of aryl halides proceeds in aqueous media under air (Scheme 8.74) [102]. 

There is no general solvent that is useful for all reactions, and BTF naturally has its limitations. In addition to the limitations posed by the freezing point, boiling point and chemical stability mentioned before, BTF is not very Lewis-basic and therefore is not a good substitute for reactions that require solvents like ethers, DMF, DMSO, etc. Not surprisingly, ions are not readily dissolved in BTF and many types of anionic reactions do not work well in BTF. For example, attempted deprotonations of esters and ketones with LDA in BTF were not successful. Reaction of diethyl malonate with NaH (5 equiv) and reaction with Mel[72] (6 equiv) in BTF was very heterogeneous and yielded 60% of the di-methylated product, compared to 89% in THF. No reaction was observed if the same malonate anion was used as a nucleophile in a Pd-catalyzed allylic substitution reaction in BTF (see 3.7). Wittig reactions also did not work very well in BTF. The ylid of ethyl triphenyl phosphonium bromide [73] was formed only slowly in BTF, and the characteristic deep red color was never obtained. 

Allylic ethers and alcohols have long been known to react with Grignard reagents in the presence of an appropriate Ni-based complex containing phosphine ligands [26]. These reactions are related to the well-studied Pd-catalyzed allylic substitution reactions that utilize soft nucleophiles [27], and a number of important mechanistic studies on the stereochemical outcome of this class of transformations have been carried out [28]. 

As discussed in Sect. 3, the mechanism of Pd-catalyzed allylic substitutions is often highly complex, involving numerous intermediates and competing reaction pathways. Enantioseiection can occur early in the catalytic cycle, e.g., by enan-tioface discrimination in the substrate, or later in the nucleophilic addition step. There are reactions where the enantioselectivity-determining step changes when the substrate structure or the reaction conditions are altered. Therefore, the origin of enantioselectivity may vary from one case to another and no general mechanism of enantioseiection can be proposed. 

Ligands with coordination sites distributed over two different cyclopentadienyl units of the ferrocenyl nucleus are represented by 26, for use in the Pd-catalyzed allylic substitution. ... 

It seems somewhat puzzling to trace the recent remarkable success in attaining highly enantioselective Pd-catalyzed allylic substitution to the external nucleophilic attack as a key step. In other words, it appears a difficult task to control... 

Chiral amidine ligands bearing sulfenyl groups have been developed.ui In these cases, more electron-rich imino groups (amidines) improve the enantioselectivity and the catalytic activity in Pd-catalyzed allylic substitution in comparison with oxazolines. 

Chiral sulfur-imine ligands 14a-gf , prepared fiom commercially available (5)-valinol, have been shown to give up to 94% ee in a Pd-catalyzed allylic substitution of 1 (Scheme 8). 

Imamoto T, Nishimura M, Koide A, Yoshida K (2007) t-Bu-QuinoxP ligand applications in asymmetric Pd-catalyzed allylic substitution and Ru-catalyzed hydrogenation. J Org Chem 72 7413-7416... 

As a further extension, the You group reported a highly efficient synthesis of planar chiral ferrocenes via Pd-catalyzed annulation reactions of diary-lethynes (Scheme 5.11). The commercially available Af-Boc-L-Val-OH proved to be an efficient ligand with air as the sole oxidant. Ferrocenes with planar chirality could be synthesized with excellent enantioselectivity and moderate yields. A more sterically demanding P,N-ligand was easily prepared and showed enhanced enantioselective control in Pd-catalyzed allylic substitution reactions. 

My personal interest in asymmetric catalysis can be dated back to my graduate study under the supervision with Professor Li-Xin Dai at the Shanghai Institute of Organic Chemistry, where my Ph.D. thesis had been focused on the synthesis of (planar) chiral ferrocene ligands and their application in Pd-catalyzed allylic substitution reactions. Since my independent research was started in 2006, our group has been focusing on asymmetric direct functionalization reactions of various C—H bonds, including Pd-catalyzed... 

A. Pfaltz Pd-catalyzed allylic substitution and Dids-Alder reactions fast MS screening of effective chiral ligands or catalysts for stereoselective reactions was achieved. [245-247]... 

Pd-catalyzed allylic substitution reactions can cover a wide range of nucleophiles, leaving groups, and substratesJ The prototype reaction is provided by the conversion of allyl acetate 1 into the substitution product IP In this case, the nucleophile 3 is an enolate derived from malonate and provides a typical example of a stabilized nucelophile (Scheme 1). 

The generally accepted mechanism for Pd-catalyzed allylic substitution involves association of the palladium(0) catalyst to the substrate, and oxidative addition to provide a ir-aUyl complex. The equilibrium between the neutral 7r-allyl complex and the more reactive cationic 7r-allyl complex depends on the nature/concentration of phosphine Ugand. Nucleophilic addition to the ligand involves direct attack on the ligand when stabilized enolates are employed. After dissociation of the product, the palladium is able to continue in the next catalytic cycle (Scheme 2). In general, the reaction proceeds via a Pd(0)/Pd(II) shuttle, although a Pd(II)/Pd(IV) pathway is also possible. 

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