Mechanistic Studies on the Copper-Catalyzed N-Arylation of Alkylamines Promoted by Organic Soluble Ionic Bases

Simon Sung,D Christopher Braddock,David Sale,Robert P Davies,Colin Brennan,Alan Armstrong

doi:10.1021/acscatal.6b00504

Simon Sung, D Christopher Braddock + Show 4 more

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https://doi.org/10.1021/acscatal.6b00504

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Abstract

Experimental studies on the mechanism of copper-catalyzed amination of aryl halides have been undertaken for the coupling of piperidine with iodobenzene using a Cu(I) catalyst and the organic base tetrabutylphosphonium malonate (TBPM). The use of TBPM led to high reactivity and high conversion rates in the coupling reaction, as well as obviating any mass transfer effects. The often commonly employed O,O-chelating ligand 2-acetylcyclohexanone was surprisingly found to have a negligible effect on the reaction rate, and on the basis of NMR, calorimetric, and kinetic modeling studies, the malonate dianion in TBPM is instead postulated to act as an ancillary ligand in this system. Kinetic profiling using reaction progress kinetic analysis (RPKA) methods show the reaction rate to have a dependence on all of the reaction components in the concentration range studied, with first-order kinetics with respect to [amine], [aryl halide], and [Cu]total. Unexpectedly, negative first-order kinetics in [TBPM] was observed...

Highlights

The classic copper-mediated cross-coupling reaction between aryl halides and amines to form C−N bonds, as first reported by Ullmann, has many drawbacks including high copper loadings, high reaction temperatures, and long reaction times.1 Recently, protocols that employ bidentate nitrogen- and oxygen-based ancillary ligands, such as 1,10-phenanthroline,2 1,3-diketones,3 and amino acids,4 have overcome some of these issues and enabled the cross-coupling reactions to be carried out under milder reaction temperatures (≤110 °C) with lower copper loadings (≤10%) (Scheme 1).5 The relatively low cost and low toxicity of copper, the use of cheap and low molecular weight ancillary ligands, and good functional group tolerance have made this reaction an attractiveScheme 1
Complex 8 has a 1:1:1 ratio of ancillary ligand, copper(I), and deprotonated nucleophile, which is in accordance with the general structure of proposed catalytic resting state species in other copper-catalyzed C−N crosscoupling reactions.9a,10a,b,14b,25b As the radical probe 10 had no effect on the aryl amination reaction, aryl halide activation of iodobenzene (2) is proposed to occur via an oxidative addition/reductive elimination mechanism to give arylamine product 3 and regenerate complex 6
In order to build a better understanding of the mechanism of copper catalyzed amination reactions, experimental mechanistic studies have been undertaken on the representative C−N crosscoupling reaction between piperidine (1) and iodobenzene (2) using a Cu(I) catalyst

Summary

■ INTRODUCTION

The classic copper-mediated cross-coupling reaction between aryl halides and amines to form C−N bonds, as first reported by Ullmann, has many drawbacks including high (often stoichiometric) copper loadings, high reaction temperatures, and long reaction times. Recently, protocols that employ bidentate nitrogen- and oxygen-based ancillary ligands, such as 1,10-phenanthroline,2 1,3-diketones, and amino acids, have overcome some of these issues and enabled the cross-coupling reactions to be carried out under milder reaction temperatures (≤110 °C) with lower copper loadings (≤10%) (Scheme 1). The relatively low cost and low toxicity of copper, the use of cheap and low molecular weight ancillary ligands, and good functional group tolerance have made this reaction an attractive. The classic copper-mediated cross-coupling reaction between aryl halides and amines to form C−N bonds, as first reported by Ullmann, has many drawbacks including high (often stoichiometric) copper loadings, high reaction temperatures, and long reaction times.. Computationally derived mechanisms for the copper-catalyzed C−N cross coupling between aryl halides and amines have been proposed in the literature, experimentally obtained mechanistic information is still scarce. A number of experimental studies have probed the structures and behavior of intermediates in the catalytic cycle, and the three-coordinate copper(I) amide catalyst resting state (Complex I, Scheme 2) has been proposed as a key catalytic intermediate in a number of literature reports.. Reactivity studies have shown aryl halide activation likely proceeds via direct oxidative addition of the aryl halide with this catalyst resting state.9,10b Kinetic studies on the coppercatalyzed C−N cross coupling reaction have been used A number of experimental studies have probed the structures and behavior of intermediates in the catalytic cycle, and the three-coordinate copper(I) amide catalyst resting state (Complex I, Scheme 2) has been proposed as a key catalytic intermediate in a number of literature reports. In addition, reactivity studies have shown aryl halide activation likely proceeds via direct oxidative addition of the aryl halide with this catalyst resting state.9,10b Kinetic studies on the coppercatalyzed C−N cross coupling reaction have been used

■ RESULTS AND DISCUSSION

■ CONCLUSION

■ REFERENCES