Oxidative addition aryl halides, amination reactions

Aromatic carboxylic acids, a,/f-unsaturated carboxylic acids, their esters, amides, aldehydes and ketones, are prepared by the carbonylation of aryl halides and alkenyl halides. Pd, Rh, Fe, Ni and Co catalysts are used under different conditions. Among them, the Pd-catalysed carbonylations proceed conveniently under mild conditions in the presence of bases such as K2CO3 and Et3N. The extremely high toxicity of Ni(CO)4 almost prohibits the use of Ni catalysts in laboratories. The Pd-catalysed carbonylations are summarized in Scheme 3.9 [215], The reaction is explained by the oxidative addition of halides, and insertion of CO to form acylpalladium halides 440. Acids, esters, and amides are formed by the nucleophilic attack of water, alcohols and amines to 440. Transmetallation with hydrides and reductive elimination afford aldehydes 441. Ketones 442 are produced by transmetallation with alkylmetal reagents and reductive elimination. 

Carbon-carbon bond formation reactions and the CH activation of methane are another example where NHC complexes have been used successfully in catalytic applications. Palladium-catalysed reactions include Heck-type reactions, especially the Mizoroki-Heck reaction itself [171-175], and various cross-coupling reactions [176-182]. They have also been found useful for related reactions like the Sonogashira coupling [183-185] or the Buchwald-Hartwig amination [186-189]. The reactions are similar concerning the first step of the catalytic cycle, the oxidative addition of aryl halides to palladium(O) species. This is facilitated by electron-donating substituents and therefore the development of highly active catalysts has focussed on NHC complexes. 

Several studies were performed in order to establish the mechaiusm (5-7). The currently accepted mechartism, presented in Scheme 26.1 for the Pd(BINAP) catalyzed amination, involves the formation of a complex, Pd(BINAP)2 from a catalyst precursor (usually Pd(OAc)2 or Pd2(dba)3) and ligand this complex lies outside the catalytic cycle and undertakes dissociation of one BINAP to form Pd(BINAP) the following steps are the oxidative addition of the aryl halide to the Pd(BINAP), reaction with amine and base, and the reductive elimination of the product to reform Pd(BlNAP). 

There are a number of procedures for coupling of terminal alkynes with halides and sulfonates, a reaction that is known as the Sonogashira reaction.161 A combination of Pd(PPh3)4 and Cu(I) effects coupling of terminal alkynes with vinyl or aryl halides.162 The reaction can be carried out directly with the alkyne, using amines for deprotonation. The alkyne is presumably converted to the copper acetylide, and the halide reacts with Pd(0) by oxidative addition. Transfer of the acetylide group to Pd results in reductive elimination and formation of the observed product. 

In addition, complexes of P(/-Bu)3 have been shown to catalyze the formation of diaryl heteroarylamines from bromothiophenes.224 Aminations of five-membered heterocyclic halides such as furans and thiophenes are limited because their electron-rich character makes oxidative addition of the heteroaryl halide and reductive elimination of amine slower than it is for simple aryl halides. Reactions of diarylamines with 3-bromothiophenes occurred in higher yields than did reactions of 2-bromothiophene, but reactions of substituted bromothiophenes occurred in more variable yields. The yields for reactions of these substrates in the presence of catalysts bearing P(/-Bu)3 as ligand were much higher than those in the presence of catalysts ligated by arylphosphines. 

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. 

Aminations of five-membered heterocyclic halides, such as furans and thiophenes, are limited. These substrates are particularly electron-rich. As a result, oxidative addition of the heteroaryl halide and reductive elimination of the amine are slower than for simple aryl halides (see Sections 4.7.1 and 4.7.3). In addition, the amine products can be air-sensitive and require special conditions for their isolation. Nevertheless, Watanabe has reported examples of successful couplings between diarylamines and bromothiophenes [126]. Triaryl-amines are important for materials applications because of their redox properties, and these particular triarylamines should be especially susceptible to electrochemical oxidation. Chart 1 shows the products formed from the amination of bromothiophenes and the associated yields. As can be seen, 3-bromothiophene reacted in higher yields than 2-bromothiophene, but the yields were more variable with substituted bromothiophenes. In some cases, acceptable yields for double additions to dibromothiophenes were achieved. These reactions all employed a third-generation catalyst (vide infra), containing a combination of Pd(OAc)2 and P(tBu)3. The yields for reactions of these substrates were much higher in the presence of this catalyst than they were in the presence of arylphosphine ligands. 

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]. 

The mechanism of the amines or alcohols arylation catalyzed by nickel(II) complexes has not been elucidated until now (refs. 7, 17), even though the arylation of nucleophiles catalyzed by nickel(0) complexes is better understood. In this last case it is generally admitted that the reaction proceeds by an oxidative addition step, followed by a nucleophilic substitution, and then a reductive elimination of the arylation product (Scheme 4). According to the work of Kochi (ref. 18), the oxidative addition of the haloarene on a nickel(O) complex takes place through a monoelectronic transfer from the metal to the aryl halide with simultaneous formation of a nickel(I) intermediate, the actual catalyst of the reaction (ref. 6). 

Terminal alkynes can be coupled directly to aryl, heteroaryl, and vinyl halides or triflates in the presence of a Pd-catalyst and a base, which frequently is an amine acting both as solvent and as scavanger for the respective acid formed in the reaction. The mechanism appears to involve oxidative addition of the sp2-halide or triflate to Pd(0), followed by alkynylation of the intermediate organopalladium complex and reductive elimination of the substituted alkyne. Copper(I) iodide is a particular effective cocatalyst, allowing the reaction to proceed at room temperature (91MI2). 

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. 

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