[Ir(COD)Cl]<sub>2</sub> as a Catalyst Precursor for the Intramolecular Hydroamination of Unactivated Alkenes with Primary Amines and Secondary Alkyl- or Arylamines: A Combined Catalytic, Mechanistic, and Computational Investigation
2010-01-13T00:00:00Z (GMT) by
The successful application of [Ir(COD)Cl]<sub>2</sub> as a precatalyst for the intramolecular addition of primary as well as secondary alkyl- or arylamines to unactivated olefins at relatively low catalyst loading is reported (25 examples), along with a comprehensive experimental and computational investigation of the reaction mechanism. Catalyst optimization studies examining the cyclization of <i>N</i>-benzyl-2,2-diphenylpent-4-en-1-amine (<b>1a</b>) to the corresponding pyrrolidine (<b>2a</b>) revealed that for reactions conducted at 110 °C neither the addition of salts (N<sup><i>n</i></sup>Bu<sub>4</sub>Cl, LiOTf, AgBF<sub>4</sub>, or LiB(C<sub>6</sub>F<sub>5</sub>)<sub>4</sub>·2.5OEt<sub>2</sub>) nor phosphine coligands served to enhance the catalytic performance of [Ir(COD)Cl]<sub>2</sub>. In this regard, the rate of intramolecular hydroamination of <b>1a</b> employing [Ir(COD)Cl]<sub>2</sub>/<b>L2</b> (<b>L2</b> = 2-(di-<i>t</i>-butylphosphino)biphenyl) catalyst mixtures exhibited an inverse-order dependence on <b>L2</b> at 65 °C, and a zero-order rate dependence on <b>L2</b> at 110 °C. However, the use of 5 mol % HNEt<sub>3</sub>Cl as a cocatalyst was required to promote the cyclization of primary aminoalkene substrates. Kinetic analysis of the hydroamination of <b>1a</b> revealed that the reaction rate displays first order dependence on the concentration of Ir and inverse order dependence with respect to both substrate (<b>1a</b>) and product (<b>2a</b>) concentrations; a primary kinetic isotope effect (<i>k</i><sub>H</sub>/<i>k</i><sub>D</sub> = 3.4(3)) was also observed. Eyring and Arrhenius analyses for the cyclization of <b>1a</b> to <b>2a</b> afforded Δ<i>H</i><sup>⧧</sup> = 20.9(3) kcal mol<sup>−1</sup>, Δ<i>S</i><sup>⧧</sup> = −23.1(8) cal/K·mol, and <i>E</i><sub>a</sub> = 21.6(3) kcal mol<sup>−1</sup>, while a Hammett study of related arylaminoalkene substrates revealed that increased electron density at nitrogen encourages hydroamination (ρ = −2.4). Plausible mechanisms involving either activation of the olefin or the amine functionality have been scrutinized computationally. An energetically demanding oxidative addition of the amine N−H bond to the Ir<sup>I</sup> center precludes the latter mechanism and instead activation of the olefin CC bond prevails, with [Ir(COD)Cl(substrate)] <b>M1</b> representing the catalytically competent compound. Notably, such an olefin activation mechanism had not previously been documented for Ir-catalyzed alkene hydroamination. The operative mechanistic scenario involves: (1) smooth and reversible nucleophilic attack of the amine unit on the metal-coordinated CC double bond to afford a zwitterionic intermediate; (2) Ir−C bond protonolysis via stepwise proton transfer from the ammonium unit to the metal and ensuing reductive elimination; and (3) final irreversible regeneration of <b>M1</b> through associative cycloamine expulsion by new substrate. DFT unveils that reductive elimination involving a highly reactive and thus difficult to observe Ir<sup>III</sup>-hydrido intermediate, and passing through a highly organized transition state structure, is turnover limiting. The assessed effective barrier for cyclohydroamination of a prototypical secondary alkylamine agrees well with empirically determined Eyring parameters.