Buchwald palladium -catalyzed oxidative

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. 

Oxidative addition of a C-X bond to a metal is of centtal importance to organometallic chemistry and specially to its application in organic synthesis. Apart from the classic Grignard synthesis of RMgX and related species, a multitude of palladium catalyzed reactions (Mizoroki-Heck, Suzuki-Miyaura, Hartwig-Buchwald. ..) go by this initial step. 

Although not directly relevant to this review, it should be noted that Sanford, Shi and Buchwald have also reported a palladium-catalyzed reaction for the chemo-and regioselective oxidative cross-coupling between ligand coordinated L-Cat-H substrates and simple arenes (Ar-H) [55-57]. 

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... 

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... 

One of the most versatile approaches to highly functionalized carbazoles is the sequential palladium-catalyzed C-N/C-C coupling for assembly of the central pyrrole moiety. Many total syntheses of naturally occurring carbazole alkaloids are following this route. The initial C-N bond formation by a palladium(0)-cata-lyzed Buchwald-Hartwig amination of aryl halides or triflates 94 with arylamines 31 affords the diarylamines 95 (Scheme 24) [139,140]. Oxidative cyclization of the diarylamines 95 to the carbazoles 32 proceeds via a double C-H bond activation and is achieved in the presence of palladium(ll) compounds. 

Clausine V (151) was prepared in two steps (Scheme 32) [150]. Buchwald-Hartwig coupling of /n-anisidine (113) with 3-bromoanisole afforded the diaryla-mine 150. Different reaction conditions have been tried for the subsequent palladium(ll)-catalyzed oxidative cychzation to clausine V (151) (Table 3). Application of 0.1 equiv. of palladium(ll) acetate and 0.1 equiv. of copper(ll) acetate in glacial acetic acid under an oxygen atmosphere gave the best result for the catalytic process (49% yield). The turnover number of almost 5 confirmed that the system works in a catalytic mode. However, in this case the best yield (67%) was obtained using stoichiometric amounts of palladium(ll) acetate in air without co-oxidant. 

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. 

Limited studies are focused on the coupling of primary and secondary phosphines with aryl electrophiles due to palladium-catalyzed aerobic oxidation of R PH to R PCO) [225], Palladium-catalyzed cross-coupling of primary or secondary phosphines has been reported with aryl iodides (Scheme 20.67) [226,227], Buchwald and coworkers utilized Pd(OAc)j-DTPF for the coupling of secondary aryl phosphines with aryl halides [256]. This system is also effective for the reaction of phosphines with aryl chlorides. 

Transmetallation is also a key step in the palladium-catalyzed Buchwald-Hartwig-Miura arylation of carbonyl compounds [171] with its manifold stereoselective variants [172]. In the general catalytic cycle, illustrated in Scheme 2.53, a ketone enolate 179 [173] reacts with the palladium(II) intermediate 178, resulting from oxidative addition, in a transmetallation step to give palladium enolates that are assumed to exist as an equilibrium between C-bond tautomer 180 and O-bound 181. Their reductive elimination under regeneration of the palladium(O) catalyst and concomitant release of the a-arylated ketone 182 closes the catalytic cycle. 

Buchwald reported the same process but as applied to vinyl triflates and nonaflates. In this case, TMSCF3 or TESCF3 was combined with KF or RbF to provide the CF3 anion, which would transfer on to the metal centre. Liu reported the palladium catalyzed indole C-2 trifluoromethylation which is proposed to proceed through a Pd(ii)/Pd(iv) cycle whereby bisacetox-yiodobenzene serves as oxidant.Also reported was the bis-functionalisa-tion of alkenes, specifically resulting in the formation of trifluoromethylated oxindoles (Scheme 15.115). It was found that addition of ytterbium triflate served to increase yields. 

---