Mechanistic studies on the copper-catalyzed N-arylation of amides

Abstract

The copper-catalyzed N-arylation of amides, i.e., the Goldberg reaction, is an efficient method for the construction of products relevant to both industry and academic settings. Herein, we present mechanistic details concerning the catalytic and stoichiometric N-arylation of amides. In the context of the catalytic reaction, our findings reveal the importance of chelating diamine ligands in controlling the concentration of the active catalytic species. The consistency between the catalytic and stoichiometric results suggests that the activation of aryl halides occurs through a 1,2-diamine-ligated copper(I) amidate complex. Kinetic studies on the stoichiometric N-arylation of aryl iodides using 1,2-diamine ligated Cu(I) amidates also provide insights into the mechanism of aryl halide activation.

Figure 1

A representative heat flow versus time profile for the CuI/3 catalyzed N-arylation of 2-pyrrolidinone with 3,5-dimethyliodobenzene and comparison of conversion data obtained from heat flow to that obtained by GC measurements. Data sampling occurred at a rate of 4 min⁻¹. Conditions: [1]₀= 0.4 M, [2]₀ = 0.8 M, [K₃PO₄]₀ = 2.4 mmol²⁵, [CuI] = 0.02 M, [3] = 0.04 M in 2.0 mL of toluene at 90 ° C.

Figure 2

Reaction rate at 50% conversion of 1 vs. [1,2-diamine] in the N-arylation of 2 (0.8 M) with 1 (0.4 M) using [CuI] (0.02 M) at 90 ° C. The curve fit reflects a nonlinear least squares fit to a function: rate = C₁[l,2-diamine]/(C₂ + [1,2-diamine])

Figure 3

Crystal structure of the dimeric 1,2-diamine-ligated CuI complex.

Figure 4

Dependence of the reaction rate on catalyst concentration at both (a) low [3] (Cu:3 =1:2) and (b) high [3] (Cu:3 = 1:7). In both cases the reaction rate displays a first-order dependence on catalyst concentration, i.e., rate ∝ [catalyst] or rate/[catalyst] = constant. Conditions: [CuI] = 0.01 – 0.04 M, [3] = 0.04 – 0.22 M, [1]_o = 0.4 M, [2]_o = 0.8 M, [K₃PO₄]_o = 2.4 mmol, 2 mL of toluene, 90 °C.

Figure 5

Dependence of the reaction rate on amide concentration ([2]) at both (a) low [3] (Cu:3 = 1:2) and (b) high [3] (Cu:3 = 1:10). Conditions: (a) [3] = 0.04 M and (b) [3] = 0.2 M, [CuI] = 0.02, [1]_o = 0.4 M, [2]_o = 0.93 M (), 0.8 M (△), 0.7 M (), 0.6 M (), [K₃P0₄]_o = 2.4 mmol, 2 mL of toluene, 90 °C. The black curves represent the nonlinear least-squares fit to eq. 9. The kinetic parameters are: K₁ = 0.85 ± 0.05, K₂ = 2.0 ± 0.2, k_act = 12 ± 3 M⁻¹•min⁻¹.

Figure 6

Dependence of the reaction rate on aryl iodide concentration ([1]) at both (a) low [3] = 0.04 M (Cu:3 = 1:2) and (b) high [3] = 0.2 M (Cu:3 = 1:10). Conditions: [CuI] = 0.02, [1]_o = 0.4 M (), 0.61 M (), 0.79 M (□), [2]_o = 0.83 M, [K₃PO₄]_o = 2.4 mmol, 2 mL of toluene, 90 °C.

Figure 7

Dependence of the reaction rate on K₃PO₄ concentration at both (a) low [3] (Cu:3 =1:2) and (b) high [3] (Cu:3 = 1:10). Conditions: (a) [3] = 0.04 M and (b) [3] = 0.2 M, [CuI] = 0.02 M, [1]_o = 0.4 M, [2]_o = 0.83 M, [K₃PO₄]_o = 1.4–3.8 mmol, 2 mL of toluene, 90 °C.

Figure 8

Hammett plot derived from the observed rate constants of the N-arylation of 2-pyrrolidinone (2) with a series of para-substituted aryl iodides. Conditions: [CuI] = 0.02, [3] = 0.04 and 0.2 M, [aryl iodide]_o = 0.4 M, [2]_o = 0.83 M, [K₃PO₄]_o = 2.4 mmol, 2 mL of toluene, 90 °C. Each point is the average of the six experiments, three experiments at each high and low [3].

Figure 9

¹H NMR spectra of a solution containing a) 7 and 3 and b) just 7 in d₈ – toluene at 20 °C.

Figure 10

Linear relationship between l/[8]_t – l/[8]_o and time (s) for the N-arylation of 8 (52 mM) with 1 (52 mM) in 1 mL of d₈ – toluene at 20 °C; k_app = 2.04 × 10⁻² M⁻¹•s⁻¹.

Figure 11

Eyring plot for the N-arylation of 8 (52 mM) with 1 (52 mM) in 1 mL of toluene from 0 – 30 °C. Each point is the average of three experiments.

Figure 12

Hammett plot derived from the second-order rate constant, k_app, obtained from the N-arylation of (l,2-diamine)Cu(I) amidate (8) with a series of para-substituted aryl iodides. Conditions: [8] = 52 mM, [aryl iodide] = 52 mM, 1 mL of toluene, 20 °C. Each point is the average of three experiments.

Figure 13

Reaction rate dependence on [amide] at low [3]. The quasilinear relationship between rate/[ArI] and l/[Amide] is shown based on eq 11, with slope = 3.02 ± 0.06×l0⁻². Conditions: low [3] (10 mol % 3, 5 mol % CuI) [1]_o = 0.4 M, () [2]_o = 0.94 M, () [2]_o = 0.78 M, (□) [2]_o = 0.66 M.

Figure 14

The quasilinear relationship between rate/K₁[Amide] and [ArI]/(1+K₁ [Amide]), where K₁ is 0.85 ± 0.05, is shown based on eq 13. The slope, which is equal to k_act[Cu]_t is 0.25 ± 0.02 min⁻¹. Conditions: high [3] (70 mol % 3, 5 mol % CuI), () [2]_o = 0.8 M, [1]_o = 0.8 M, () [2]_o = 0.9 M, [1]_o = 0.6 M, () [2]_o = 0.8, [1]_o = 0.6 M, (×) [2]_o = 1.0 M, [1]_o = 0.6 M.

Figure 15

Comparison between experimental conversion vs. time data, and results obtained by numerically integrating equation 14 with k_app = 0.2 M⁻¹•s⁻¹ for different ratios of k_f : k_r (= Cu_active:Cu_inactive). Conditions: [ArI]_o = 0.4 M, [Cu_inactive]_o = 0.02 M, a) experimental [3] = 0.02 M, b) experimental [3] = 0.29 M.

Scheme 1

Simplified Catalytic Cycle Displaying the Two-Stage Cu(I)-Catalyzed N-Arylation Process.

Scheme 2

Mechanisms for the Cu(I)-Mediated Aryl Halide Activation Step.

Scheme 3

Possible Mechanisms for the Cu(I) Amidate Promoted Aryl Iodide Activation.

Scheme 4

Proposed Mechanism for the Cu(I)-Catalyzed N-Arylation of Amides.