Buchwald—Hartwig amination reaction

Palladium-catalyzed aminations of aryl halides is now a well-documented process [86-88], Heo et al. showed that amino-substituted 2-pyridones 54 and 55 can be prepared in a two-step procedure via a microwave-assisted Buchwald-Hartwig amination reaction of 5- or 6-bromo-2-benzyloxypyri-dines 50 and 51 followed by a hydrogenolysis of the benzyl ether 52 and 53, as outlined in Fig. 9 [89]. The actual microwave-assisted Buchwald-Hartwig coupling was not performed directly at the 2-pyridone scaffold, but instead at the intermediate pyridine. Initially, the reaction was performed at 150 °C for 10 min with Pd2(dba)3 as the palladium source, which provided both the desired amino-pyridines (65% yield) as well as the debrominated pyridine. After improving the conditions, the best temperature and time to use proved... 

The Buchwald-Hartwig amination reaction has gained great interest in the last decade in both academic and industrial environments. In the work presented herein, we discuss a very interesting effect in the competitive reaction of two amines (benzophenone hydrazone and n-hexylamine) with 3-bromobenzotrifluoride. 

Scheme 6.61 Buchwald-Hartwig amination reactions of aryl chlorides.

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. 

The required 5-phenoxypyridazin-3(2/7)-ones 234 and 236 are easily available through a nucleophilic substitution reaction on halopyridazin-3(2TZ)-ones 146 and 239, respectively whereas the required 5-phenylaminopyridazin-3(2//)-one 237 could be synthesized via a chemoselective Buchwald-Hartwig amination reaction on 146 with 2-bromoaniline. 

The Buchwald-Hartwig amination reaction has become a most efficient method for forming a new C-N bond, and it is mediated by a Pd catalyst. Onr group reported on the nse of 1 to catalyze amination reactions of aryl triflates with very good results (Table 14.5). ... 

Buchwald-Hartwig Amination Reactions with Aryl Triflates Using 1... 

The workers at Sepracor then added the left-hand end of the molecule (we shall call this R ) to the free OH group. The other aromatic ring, already functionalized with the right-hand end of the molecule (we shall call this R ) was coupled as its bromide to the free NH group by a second Buchwald—Hartwig amination reaction process. It s easy to see how this chemistry simplifies the assembly of such a large and complex molecule. 

Indoles can be synthesized via a palladium-mediated intramolecular amination reaction of an appropriately substituted haloarene. This is a specific application of the Buchwald-Hartwig amination reaction that has found use in the synthesis of biologically active natural products. 

The Buchwald-Hartwig amination reaction has also been applied to the synthesis of A -arylhydrazones, which can then be transformed into indoles via the Fisher indole synthesis. Since this reaction sequence does not use a Buchwald-Hartwig amination reaction directly in the synthesis of indoles, it will not be a focus of this chapter. 

The Buchwald-Hartwig amination reaction can facilitate the synthesis of nitrogen-containing heterocycles. For instance, Buchwald demonstrated that the amination reaction could be used to prepare N-arylhydrazones from hydrazones and aryl halides. Acid-catalyzed condensation of the hydrazone with a ketone then yielded the desired indoles.Hartwig described a similar arylhydrazone formation with DPPF as a ligand and CS2CO3 as a base."... 

With the development of Buchwald-Hartwig amination reactions, the amine component of these indoles can also be introduced into these precursors via palladium catalysis [8]. As shown by Ackermann, this can be coupled with aryl halide alkynylation and cyclization to provide a one-pot, three-component synthesis of substituted indoles (Scheme 6.6) [9]. In this case, simple ortho-dihaloarene derivatives S were employed as starting materials, with Sonogashira coupling occurring at the more activated aryl-iodide bond, followed by selective coupling of various alkyl or arylamines. Alternatively, Zhao has recently demonstrated that amination can be performed on both bromoalkyne 6, followed by the aryl-bromide bond, to provide a route to 2-amidoindoles (Scheme 6.7) [10]. 

Nolan and coworkers reported on the excellent activity of 4 as precatalyst for the Buchwald-Hartwig amination reaction, displaying high efficiency for the coupling of numerous (hetero)aryl chlorides, at room temperature or at extremely low catalyst loading as low as 0.025 mol% [26]. 

Phosphonium-based IL-coated lipase (ILl-PS)-catalyzed reaction has been reported. ILl-PS was used as a catalyst in 2-methoxyethoxymethyl-(tri-n-butyl)-phosphonium bis(trifluoromethanesulfonyl)-amide for the transesterification of secondary alcohols [128]. McNulty et al. studied the anionic effect of Pd-catalyzed Buchwald-Hartwig amination reaction in phosphonium-based ILs [129]. Phosphonium-based ILs are also used in ... 

The GooBen group developed palladium-catalyzed Buchwald-Hartwig amination reactions of aryl chlorides using a bench-stable, commercially available A -heterocycle-based catalyst (Experimental Procedure below). ... 

In 2002, the expansion of the Buchwald-Hartwig amination reaction to alkenyl halide electrophiles was reported. This has proven to be a useful method for the construction of enamines or imines that are difficult to prepare using traditional condensation reactions [127]. For example, Voskoboynikov and coworkers [128] demonstrated that azoles could be stereoselectively coupled with either E- or Z-p-bromostyrene to generate enamines using a catalyst composed of Pd(dba)2 and P(t-Bu)3 (Eq. 15). In the same year, Mori and Kozawa reported Pd(OAc)2/DPE-Phos catalyzed intramolecular iV-aUcenylation reactions that afforded bicycUc p-lactams (Eq. 16) [129]. 

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