Industrial‐Scale Palladium‐Catalyzed Coupling of Aryl Halides and Amines –A Personal Account

Abstract

Abstract:The palladium-catalyzed coupling of amines and aryl halides or aryl alcohol derivatives has matured from an exotic small-scale transformation into a very general, efficient and robust reaction during the last ten years. This article reports several applications of this method from an industrial vantage point, including ligand synthesis, synthesis of arylpiperazines, arylhydrazines and diarylamines. Much emphasis in placed on issues of scale-up and safety to underline the potential of C À N couplings as solutions for industrial-scale synthetic problems.

Copper‐Catalyzed N‐Alkylation of Sulfonamides with Benzylic Alcohols: Catalysis and Mechanistic Studies

“…As shown in Table 1 all copper salts tested showed some activity for the conversion of p-toluenesulfon-A C H T U N G T R E N N U N G amide. For example, 20-30% conversion was obtained when CuCl, CuCl 2 , CuBr, CuCO 3 ·Cu(OH) 2 or CuBr 2 were used as catalysts (Table 1, entries 1-5). Much higher conversion, that is,~50%, was observed if 2 were applied (Table 1, entries 6-8).…”

“…[1] In the past decades, versatile catalytic procedures for carbon-nitrogen (C À N) bond formation, for instance, amination of aryl halides, [2] hydroaminations [3] and hydroaminomethylations [4] have been developed. Nevertheless, further improvements are still possible.…”

Biaryl Phosphane Ligands in Palladium‐Catalyzed Amination

“…[87,88,164,165] These workers followed the progress of the reaction by both calorimetry and in situ Raman spectroscopy. In the coupling of the model system of 4-bromotoluene with benzophenone hydrazone the structure of the ligand was crucial (Scheme 58).…”

“…The aryl magnesium halide then adds to the benzyne and the resulting Grignard reagent is treated with a dialkylchlorophosphine in the presence of a catalytic quantity of copper(I) chloride to generate the ligand (Scheme 1). [85,86] As a result of their ease of synthesis and utility a significant number of this class are now commercially available ( Figure 1) and their large scale synthesis has been investigated by Rhodia Pharma Solutions and Lanxess [87,88] and now at Shasun and Saltigo. The utility of these ligands has resulted in the introduction of structurally related variants by others [89][90][91][92][93][94][95][96][97][98][99][100][101][102][103][104][105] and has spawned innovative alternative synthetic routes by Diels-Alder reaction [96,106] and formal rhodiumcatalyzed [2+2+2] cycloaddition.…”

Highly Reactive, General and Long-Lived Catalysts for Palladium-Catalyzed Amination of Heteroaryl and Aryl Chlorides, Bromides, and Iodides: Scope and Structure–Activity Relationships

“…These reactions exceeded the maximum turnover numbers for the reactions of primary alkyl amines with aryl iodides by more than an order of magnitude. 35 Hindered, ortho-substituted aryl halides also reacted with primary alkylamines with low catalyst loadings (Table 3, entries [5][6][7][8]24). For example, the reaction of 1-bromo-2-isopropylbenzene with iso-butylamine formed the coupled product in 95% yield in DME after 48 h at 100 °C in the presence of 0.05 mol % catalyst, and the reaction of 2,6-disubstituted aryl bromides and chlorides occurred with octylamine with only 0.05-0.1 mol % catalyst.…”