Buchwald mechanism

Buchwald and co-workers56 found that ( )-olefins cycloisomerized upon exposure to [Cp2Ti(GO)2] giving exclusively the 1,4-diene Alder-ene products (Equation (46)). In contrast to the palladium conditions developed by Trost (see Section 10.12.4.1), the 1,4-diene is formed exclusively, even from substrates containing a tertiary carbon at the allylic position 75. It was noted, however, that heating the reaction mixture for an extended period of time in some instances led to olefin isomerization, forming 1,3-dienes. The mechanism of this titanium-catalyzed... 

In 1995, Buchwald and Hartwig independently discovered the direct Pd-catalyzed C—N bond formation of aryl halides with amines in the presence of stoichiometric amount of base [93, 94], This field is becoming rapidly mature and many reviews covering the scope and limitations of this animation have been published since 1995 [95-102]. In the context of heteroaryl synthesis, one example is given to showcase the utility and mechanism of this reaction. Applications to individual heterocycles may be found in their respective chapters. 

The opening step of the Buchwald-Hartwig reaction, similarly to the previous cases, is the oxidative addition of an aryl halide or sulfonate onto a low oxidation state metal. Although the term Buchwald-Hartwig reaction is usually reserved for palladium catalyzed processes, carbon-heteroatom bond formation also proceeds readily with nickel and copper. The nickel catalyzed processes follow a similar mechanism, while the distinctly different copper catalyzed reactions will be discussed in Chapter 2.5. 

A plausible mechanism for the one-pot synthesis ofcarbazoles is shown in Scheme 5. It consists of two interlinked catalytic cycles. In the first cycle a classical Buchwald-Hartwig amination reaction occurs to generate an intermediate 5 which then enters the second cycle by oxidative addition to Pd(0). The resulting Pd(II) complex then undergoes intramolecular C-H activation to give a six-membered palladacycle which subsequently yields the carbazole by reductive elimination. 

Problem 6.22. Draw a mechanism for the following Buchwald-Hartwig amination. 

Some examples of rate and binding constants for these micelle-assisted reactions are in Table 6. There are very large differences in k j /k y/ for these reactions, but the rate effects on decarboxylation are large and depend upon the charge on the head group. Reaction of 2,4-dinitrophenyl phosphate is often written as generating intermediate metaphosphate ion, but this species is so short-lived that reaction follows an enforced association mechanism (Buchwald and Knowles, 1982). 

Buchwald, Friedman and Knowles succeeded in preparing 2,4-dinitrophenyl phosphate in which the three free oxygen atoms on phosphate were labeled stereospecifically with different isotopes of oxygen. Solvolysis of this compound in methanol and analysis of the methyl phosphate product showed that the reaction had proceeded with inversion of configuration at phosphorus (79). This remarkable experiment supports a concerted bimolecular displacement mechanism, with no metaphosphate intermediate, for the solvolysis of 2,4-dinitrophenyl phosphate in methanol. However, it does not rigorously exclude a stepwise mechanism in which a metaphosphate intermediate with a very short lifetime is formed and reacts with methanol faster than it rotates, and it does not provide direct evidence for a bimolecular, concerted reaction with solvent water. 

The direct intermolecular a-arylation of relatively less acidic ketones with aryl halides, which proceeds by mechanism B, was reported concurrently in 1997 by the groups of Miura, Buchwald, and Hartwig [35-37]. The intramolecular version was also described by Muratake and coworkers in the same year [38,39], while some intermolecular vinylation reaction had been reported [40, 41]. Taking advantage of this, the reaction of carbonyl compounds and related substrates has been studied extensively. Now a variety of ketones are known to be arylated by using appropriate ligands and bases [42-46]. The reaction usually takes place at a less hindered a position (Eqs. 5-7) [19,20]. 

The mechanisms and catalysts used in this Buchwald-Hartwig chemistry mirror those of coupling reactions involving oxidative addition, transmetallation, and reductive elirruna-tion. The first step, as usual, is oxidative insertion of Pd(0) into the aryl-halogen bond. The Pd(ll) complex now adds the amine so that both coupling partners find themselves bonded to the same palladium atom. The base eliminates H—1 from the complex and reductive elimination forms the Ar—N bond. 

The mechanism of the direct intramolecular Buchwald-Hartwig indole synthesis is that of a traditional palladium-catalyzed cross-coupling reaction and begins with loss of a ligand on palladium. Oxidative addition of an appropriately substituted Z-vinylhaloarene (1) generates intermediate 2. Deprotonation of 2 and displacement of a halide ligand sets up a reductive elimination on 3 to yield indole 4. 

Detailed kinetic studies have been carried out by the groups of Hartwig, Blackmond, and Buchwald under synthetically relevant conditions to study the mechanism of the amination of an aryl bromide with primary and secondary amines using Pd complexes of binap (2,2 -bis(diphenylphosphino)-l,l -binaphthyl), among others [393]. Different mechanisms were proposed for this reaction, and a final reevaluation of the mechanism was made in collaboration between the three aforementioned groups [393c[. 

Although comparable with the Heck reaction in terms of the catalytic cocktail, the recently developed conversions of aryl bromides to arylamines (the Hartwig-Buchwald reactions) proceed by a different mechanism (Chapter 13). 

The mechanism of the Hartwig-Buchwald amination involves three basic steps oxidative addition of the aryl halide to a palladium(O) species, coordination ofa nitrogen atom to the palladium or transmetaUation, and finally, reductive elimination (Scheme 13.1). 

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