Evidence for alkene cis-aminocupration, an aminooxygenation case study: kinetics, EPR spectroscopy, and DFT calculations

Abstract

Alkene difunctionalization reactions are important in organic synthesis. We have recently shown that copper(II) complexes can promote and catalyze intramolecular alkene aminooxygenation, carboamination, and diamination reactions. In this contribution, we report a combined experimental and theoretical examination of the mechanism of the copper(II)-promoted olefin aminooxygenation reaction. Kinetics experiments revealed a mechanistic pathway involving an equilibrium reaction between a copper(II) carboxylate complex and the γ-alkenyl sulfonamide substrate and a rate-limiting intramolecular cis-addition of N-Cu across the olefin. Kinetic isotope effect studies support that the cis-aminocupration is the rate-determining step. UV/Vis spectra support a role for the base in the break-up of copper(II) carboxylate dimer to monomeric species. Electron paramagnetic resonance (EPR) spectra provide evidence for a kinetically competent N-Cu intermediate with a Cu(II) oxidation state. Due to the highly similar stereochemical and reactivity trends among the Cu(II)-promoted and catalyzed alkene difunctionalization reactions we have developed, the cis-aminocupration mechanism can reasonably be generalized across the reaction class. The methods and findings disclosed in this report should also prove valuable to the mechanism analysis and optimization of other copper(II) carboxylate promoted reactions, especially those that take place in aprotic organic solvents.

Figure 1

A linear plot of 2[1]^0.5 versus time showing half-order dependence in substrate 1.

Figure 2

Plot of k_obs against [NBu₄OAc] showing the effect of increasing the concentration of NBu₄OAc on the rate of the reaction. The rate constant is optimum at 2:1 ratio between [Cu] and [OAc⁻] (k_obs = 0.62 ± 0.05 mM^0.5 min⁻¹).

Figure 3

Structure of dimeric copper(II) acetate adducts with R = CH₃ and L could be H₂O, MeOH, acetic acid, DMF, pyridine.

Figure 4

Plot of ln (k_obs) versus ln [Cu(eh)₂]. The order in Cu(eh)₂ was obtained from the slope of the plot, 0.52 ± 0.03.

Figure 5

UV/Vis spectra of a series of Cu(eh)₂ (A) solution titrated with NBu₄OAc (B), K₂CO₃ and Cs₂CO₃.

Figure 6

EPR spectra of solutions of a) Cu(eh)₂ and Bu₄NOAc, b) Cu(eh)₂, Bu₄NOAc and sulfonamide 1 (heated at 50 °C for 15 min) and c) Cu(eh)₂ and deprotonated sulfonamide 1 in toluene at 100 K.

Figure 7

Kinetic plot of the conversion of [N–Cu] complex to 2.

Figure 8

Potential energy landscapes for the two-acetate-ligand neutral path A (blue diamond) and the one-acetate-ligand path B (red square) at 110°C. Energy scale in kcalmol⁻¹. G_TSA = 17.2 kcalmol⁻¹, G_TSB = 16.0 kcal mol⁻¹.

Figure 9

Optimized structures of aminocupration transition states, the resulting C–Cu intermediates, and spin density analysis thereof. C(1) = internal (alkene) carbon, C(2) = terminal (alkene) carbon. a) Transition state TS-A, b) intermediate I-6, c) transition state TS-B, d) intermediate I-2B.

Figure 10

Path D transition states: a) cis-chair TS, relative energy = 0 kcalmol⁻¹; b) trans-chair TS, relative energy = 3.5 kcalmol⁻¹; c) cis-boat TS, relative energy = 0.2 kcalmol⁻¹; d) trans-boat TS, relative energy = 2.7 kcalmol⁻¹. C(1) = internal carbon, C(2) = terminal carbon.

Figure 11

Path E transition states: a) cis-chair TS, relative energy = 0.2 kcalmol⁻¹; b) trans-chair TS, relative energy = 3.3 kcalmol⁻¹; c) cis-boat TS, relative energy = 0 kcalmol⁻¹; d) trans-boat TS, relative energy = 4.9 kcalmol⁻¹. C(1) = internal carbon, C(2) = terminal carbon.

Figure 12

Potential energy landscape for the two possible pathways for the aminooxygenation of -methyl–al-kenylsulfonamide 14 at 130°C (energy scale in kcalmol⁻¹).

Scheme 1

Proposed mechanisms for C–C, C–N, and C–O bond formations.

Scheme 2

Proposed mechanism for the diastereoselective, copper-promoted, aminooxygenation of substituted alkenyl sulfonamides.

Scheme 3

Proposed mechanism for the copper(II)-promoted aminooxygenation of alkenes.

Scheme 4

Evidence for direct capture of the carbon radical with TEMPO.

Scheme 5

Mechanistic alternative for copper(II)-promoted alkene aminoxygenation.

Scheme 6

Cation effects on relative energies of aminocupration activation energy. Relative energies only are being compared since different atoms are involved in each path. G_TS(C–A) = 2.8 kcalmol⁻¹.

Scheme 7

Potential reaction coordinates for the cis-pyrrolidine selective aminooxygenation reaction. Path D involves a two-acetate neutral copper(II) complex and Path E involves a one-acetate neutral copper(II) complex.