Amination of aryl halide

Intramolecular aryl halide animations were also conducted with the original catalysts [99]. For example, the reactions in Eq. (6) proceeded with yields in excess of 80 %. In this case, the halide could be iodide or bromide, and [Pd(PPh3)4] proved to be a more effective catalyst than Pd[P(o-C6H4Me)3]2Cl2.  

Second Generation Catalysts Aryl Bis-phosphines 4.3.2.1 Amination of Aryl Halides 

In papers published back-to-back in 1996, Hartwig and Buchwald reported amination chemistry with palladium complexes of DPPF and BINAP as catalysts [64, 104]. These palladium complexes facilitated aminations of aryl bromides and iodides with primary alkyl amines, with cyclic secondary amines, and with anilines. It is ironic that the amination chemistry was first discovered by using a particularly labile phosphine, but was dramatically improved by the use of tightly bound chelating ligands. 

HNRR-primary amine, cyclic secondary amine, HNMeBn, HNMePh 

DPPF-ligated palladium provided nearly quantitative yields for amination of aryl halides with anilines (Eq. (7)). Electron-rich, electron-poor, hindered or unhindered aryl bromides or iodides all participated in the amination chemistry, with only a few exceptions. Nitro haloarenes gave no amination product with aniline substrates, 

Halide Amine Product Catalyst (%) Time (h) Isolated 

Y = o-alkyl, p-CN, p-C(0)Ph, p, o-C(0)Me, p-OMe HNRR =primary amine, cyclic secondary amine, HNMeBn, HNMePh 

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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... 

Buchwald has developed a route to indolines by the Pd-catalyzed intramolecular amination of aryl halides <96T7525> and applied this method to the synthesis of natural products. Thus, cyclization of tetrahydroquinoline 70 provided 71 which was elaborated to a key intermediate in syntheses of damirones A and B and makuluvamine <96JA1028>. 

The Pd-catalyzed amination of aryl halides had rapidly become one of the most important methods to synthesize substituted aiylamines. Since its discovery in 1995, thanks to two independent studies by Buchwald and Hartwig, it has generated a... 

Scheme 26.2 Amination of aryl halides catalyzed by Pd(binap).

Figure 1 Chelating and hemilabile ligands used in palladium-catalyzed amination of aryl halides.

Complexes ligated by alkylphosphines had been used rarely as catalysts in cross-coupling chemistry, but several studies suggested that they could catalyze the amination of aryl halides with higher selectivity and activity than catalysts of arylphosphines. Steric hindrance promotes reductive elimination at the expense of /3-hydrogen elimination.54 Therefore, reactions of primary amines and, in... 

Figure 2 Carbenes that have been used, in combination with palladium, for the amination of aryl halides.

Boger and co-workers were the first to report the intramolecular amination of aryl halides in their synthesis of lavendamycin [436-438], Thus, biaryl 366 is smoothly cyclized under the action of 1.5 equivalents of Pd(PhjP)4 to P-carboline 367, which comprises the CDE rings of lavendamycin. 

Scheme 1.2 Pd-catalysed amination of aryl halides using the chiral ligand Binap.

Amination of aryl halides a. activated aryi halides... 

Yang, B.H. and Buchwald, S.L., Palladium-catalysed amination of aryl halides and sulfonates, /. Organomet. Chem., 1999,576, 125-146. 

Paul, F. Influences on the relative rates for C-N bond-forming reductive elimination and /J-hydrogen elimination of amides. A case study on the origins of competing reduction in the Pd-catalyzed amination of aryl halides. 

This chapter will cover the recent developments in palladium-catalyzed amination of aryl halides and sulfonates. The nickel-catalyzed process requires much higher catalyst loads and has a more narrow substrate scope, and will not be reviewed [70,71]. The first sections will cover the development of different palladium catalysts for the... 

Palladium-Catalyzed Amination of Aryl Halides Using Amine Substrates... 

Initial Intermolecular Tin-Free Aminations of Aryl Halides... 

In 1995, Hartwig and Buchwald published concurrently their two groups results on tin-free amination of aryl halides [79,80], Instead of isolating or generating a tin amide in situ, the amination reactions were conducted by reacting an aryl halide with the combination of an amine and either an alkoxide or silylamide base (Eq. (5)). These reactions were typically conducted between 80 and 100 °C in toluene solvent. The catalysts used initially were 1, 3, or a combination of [Pd2(dba)3] (Sa) (dba = trans, trans-dibenzylidene acetone) and P(o-C6H4Me)3. Catalysts used subsequently will be described below. As shown in Table 7.1, secondary amines were viable substrates, but primary amines gave substantial yields with... 

The amination of aryl halides and triflates catalyzed by palladium complexes is suitable for use in complex synthetic problems. Many substrates will produce high yields of mixed arylamines with one of the existing catalyst systems. Nevertheless, there are many combinations of substrates for which the amination chemistry may be substantially improved. For the most part, these reactions involve nitrogen centers, such as those in pyrroles, indoles, amides, imidazoles and other heterocyclic groups that are less basic than those in standard alkylamines. Although mild reaction conditions have been developed for many substrates, the harsh conditions used in many of the applications indicate that continued studies on developing mild condi-... 

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