[Ir(COD)Cl]2 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

Abstract

The successful application of [Ir(COD)Cl](2) 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 N-benzyl-2,2-diphenylpent-4-en-1-amine (1a) to the corresponding pyrrolidine (2a) revealed that for reactions conducted at 110 degrees C neither the addition of salts (N(n)Bu(4)Cl, LiOTf, AgBF(4), or LiB(C(6)F(5))(4) x 2.5 OEt(2)) nor phosphine coligands served to enhance the catalytic performance of [Ir(COD)Cl](2). In this regard, the rate of intramolecular hydroamination of 1a employing [Ir(COD)Cl](2)/L2 (L2 = 2-(di-t-butylphosphino)biphenyl) catalyst mixtures exhibited an inverse-order dependence on L2 at 65 degrees C, and a zero-order rate dependence on L2 at 110 degrees C. However, the use of 5 mol % HNEt(3)Cl as a cocatalyst was required to promote the cyclization of primary aminoalkene substrates. Kinetic analysis of the hydroamination of 1a revealed that the reaction rate displays first order dependence on the concentration of Ir and inverse order dependence with respect to both substrate (1a) and product (2a) concentrations; a primary kinetic isotope effect (k(H)/k(D) = 3.4(3)) was also observed. Eyring and Arrhenius analyses for the cyclization of 1a to 2a afforded DeltaH(double dagger) = 20.9(3) kcal mol(-1), DeltaS(double dagger) = -23.1(8) cal/K x mol, and E(a) = 21.6(3) kcal mol(-1), while a Hammett study of related arylaminoalkene substrates revealed that increased electron density at nitrogen encourages hydroamination (rho = -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(I) center precludes the latter mechanism and instead activation of the olefin C=C bond prevails, with [Ir(COD)Cl(substrate)] M1 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 C=C 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 M1 through associative cycloamine expulsion by new substrate. DFT unveils that reductive elimination involving a highly reactive and thus difficult to observe Ir(III)-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.