Palladium-catalyzed amination oxidative addition

A general mechanism for the palladium-catalyzed amination of aryl halides is presented in Scheme 7. This picture has been developed from studies performed largely upon isolated complexes, with the oxidative addition and reductive elimination steps being investigated in the greatest detail. On... 

Palladium-catalyzed amination is an attractive alternative strategy to the current synthesis of fluoroquinolones because the reaction goes through an oxidative addition step in which aryl-fluoride bonds are inert. This reaction involves an efficient coupling of aryl halides and amines (eq 1) and is successful for aryl halides with a broad range of functionalities. In this paper, we report model studies of the palladium-catalyzed amination of fluorohaloarenes to produce fluoroam-lines. Indeed, the model studies demonstrate that the catalytic reaction is chemo-selective. Moreover, in this paper, we demonstrate that the palladiiun-catalyzed amination methodology can be extended toward chemoselective syntheses of fluoroquinolones. 

The palladium catalyzed amination of aryl triflates has proved to be a more challenging problem. Aryl triflates are less favored to undergo oxidative addition as compared to aryl bromides and iodides. Another, more daunting, challenge with aryl triflates is their proclivity to react with NaOt-Bu at sulfur to give a sodium phenoxide as the major by-product. Buchwald s laboratory reported that with fairly electron rich (EDG) and neutral aryl triflates, they could use NaO/-Bu as a base with minor amounts of... 

The 2,3-substituted indols are formed via a palladium-catalyzed coupling reaction of aryl halide, o-alkenylphenyl isocyanide, and amine (Equation (122)).481 Oxidative addition of an aryl halide, insertion of both the isonitrile and alkene moieties of o-alkenylphenyl isocyanide, and 1,3-hydrogen migration may form a 7r-allylpalladium species, which is then attacked by an amine to afford an indol. 

The Pd-catalyzed amination of / -rm-butylphenyl bromide with pyrrole in the presence of Pd(OAc)2, dppf and one equivalent of NaOr-Bu led to the Af-arylation product 88. A simplified version of the mechanism commences with the oxidative addition of p-te/t-butylphenyl bromide to Pd(0), giving rise to the palladium complex 89. Ligand exchange with pyrrole followed by deprotonation by the base (NaOr-Bu) results in amido complex 90. Reductive elimination of 90 then gives the amination product 88 with concomitant regeneration of Pd(0) catalyst. If the amine had a (3-hydride in amido complex 90, a (3-hydride elimination would be a competing pathway, although reductive elimination is faster than P-hydride elimination in most cases. 

Palladium-catalyzed addition of oxygen nucleophiles to alkenes dates back to the Wacker process and acetoxylation of ethylene (Sects. 1 and 2). In contrast, catalytic methods for intermolecular oxidative amination of alkenes (i.e., aza-Wacker reactions) have been identified only recently. Both O2 and BQ have been used as oxidants in these reactions. 

Bulky ligands as above have also proved to be effective in other palladium-catalyzed reactions of aryl halides, e.g., amination [16-19], Suzuki-Miyaura reaction [20-22], Mizoroki-Heck reaction [23, 24], Migita-Kosugi-Stille reaction [25], and aryloxylation and alkoxylation [26-28] as well as the reaction with various carbon nucleophiles as described below. The ligands are considered to enhance both the initial oxidative addition of aryl halides and the reductive elimination of products [29, 30]. The effectiveness of the commercially available simple ligand, P(f-Bu)3, was first described for the amination by Nishiyama et al. [16]. 

Heterocycles - Aromatic substitution via N-oxides has been reviewed.51 Palladium catalyzed intramolecular addition of amines to olefins has resulted in new syntheses of indoles52-3 and isoquinuclidines.53... 

A wide variety of nucleophiles add to an -rf-allyl ligand. Desirable nucleophiles typically include stabilized carbanions such as CH(COOR)2 or 1° and II0 amines. Unstabilized nucleophiles such as MeMgBr or MeLi often attack the metal first and then combine with the n-allyl by reductive elimination. The Tsuji-Trost reaction, which is typified by the addition of stabilized carbanions to T 3—allyl ligands complexed to palladium followed by loss of the resulting substituted alk-ene, comprises an extremely useful method of constructing new C-C bonds, and many applications of this reaction have appeared in the literature.61 Equation 8.43 illustrates an example of a Pd-catalyzed addition of a stabilized enolate to an allyl acetate.62 The initial step in the catalytic cycle is oxidative addition of the allyl acetate to the Pd(0) complex, followed by nq1 to nq3—allyl isomerization, and then attack by the nucleophile to a terminal position of the T 3—allyl ligand. We will discuss the Tsuji-Trost reaction, especially in regard to its utility in chiral synthesis,63 more extensively in Chapter 12. 

In the dimerization reaction of butadiene catalyzed by palladium complexes, nucleophiles (YH), such as amines, alcohols, phenols, carboxylic acids 41 4S>, and active methylene compounds 46) are introduced. This reaction can be explained by the attack of these nucleophiles on the jr-allylic complexes formed as intermediates-in the reactions. Takahashi, Shibano, and Hagihara confirmed by using deuterium that the hydrogen of YH migrates to C6 of the dimeric product, probably via the oxidative addition reactions of YH to the palladium species 42). 

The generally accepted catalytic cycle for the Buchwald-Hartwig amination mirrors that of other palladium catalyzed cross-coupling reactions.10 11 irThere is an oxidative addition (A to B), followed by an exchange on palladium (B to C), and finally a reductive elimination (C to D and A). The main difference involves the exchange step. In a Suzuki, or Stille, reaction this step proceeds through a discrete transmetallation event, whereas... 

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