Mechanism of the Stereoselective α-Alkylation of Aldehydes Driven by the Photochemical Activity of Enamines

Abstract

Herein we describe our efforts to elucidate the key mechanistic aspects of the previously reported enantioselective photochemical α-alkylation of aldehydes with electron-poor organic halides. The chemistry exploits the potential of chiral enamines, key organocatalytic intermediates in thermal asymmetric processes, to directly participate in the photoexcitation of substrates either by forming a photoactive electron donor-acceptor complex or by directly reaching an electronically excited state upon light absorption. These photochemical mechanisms generate radicals from closed-shell precursors under mild conditions. At the same time, the ground-state chiral enamines provide effective stereochemical control over the enantioselective radical-trapping process. We use a combination of conventional photophysical investigations, nuclear magnetic resonance spectroscopy, and kinetic studies to gain a better understanding of the factors governing these enantioselective photochemical catalytic processes. Measurements of the quantum yield reveal that a radical chain mechanism is operative, while reaction-profile analysis and rate-order assessment indicate the trapping of the carbon-centered radical by the enamine, to form the carbon-carbon bond, as rate-determining. Our kinetic studies unveil the existence of a delicate interplay between the light-triggered initiation step and the radical chain propagation manifold, both mediated by the chiral enamines.

Figure 1

Enamine reactivity domains. Ground-state reactivity: enamines as (a) nucleophiles in traditional polar processes and (b) radical precursors upon single-electron chemical oxidation. Excited-state domain: enamines can drive the photochemical generation of radicals by (c) inducing the formation of ground-state, photoactive EDA complexes and (d) acting as a photoinitiator upon direct light excitation. SET = single-electron transfer. So = SOMO-phile that can intercept the enamine radical cation. The gray circle represents the chiral organic catalyst scaffold.

Figure 2

Model photochemical alkylations of butanal (1a) catalyzed by the chiral secondary amine A: enamine-based EDA complex activation in the reaction of (a) 2,4-dinitrobenzyl bromide (2a) and (b) phenacyl bromide (2b); (c) direct photoexcitation of enamines in the alkylation of 1a with diethyl bromomalonate (2c). MTBE = methyl tert-butyl ether. NMR yield of 3 determined by ¹H NMR spectroscopic analysis of the crude reaction mixture using 1,1,2-trichloroethene as the internal standard. The asterisk indicates the yield of the isolated products 3.

Figure 3

(a) Optical absorption spectra, recorded in MTBE in 1 mm path quartz cuvettes using a Shimadzu 2401PC UV–vis spectrophotometer, and visual appearance of the separate reaction components and of the colored EDA complex in the alkylation of 2,4-dinitrobenzyl bromide (2a). [1a] = 1.5 M, [2a] = 0.5 M, and [A] = 0.1 M. (b) Optical absorption spectra in MTBE for the alkylation with phenacyl bromide (2b). [1a] = 1.5 M and [2b] = [A] = 0.2 M. (c) Investigating the formation of the EDA complexes in MTBE using the preformed enamine 4. K_EDA is the association constant for the EDA complex formation. E_p^red for 2a and 2b (irreversible reduction) and E_p^ox for 4 (irreversible oxidation) measured by cyclic voltammetry vs Ag/Ag⁺ in CH₃CN. (d) Visible-light-triggered generation of the electrophilic carbon-centered radical IV and the α-iminyl radical cation V using the enamine-based EDA complex strategy. hν_CT = charge-transfer transition energy. BET = back electron transfer.

Figure 4

Optical absorption spectra acquired in MTBE in 1 cm path quartz cuvettes. [1a] = 1.5 M, [2c] = 0.5 M, and [A] = 0.1 M.

Figure 5

Radical generation strategy based on the direct photoexcitation of the chiral enamine I. The gray circle represents the chiral organic catalyst scaffold.

Figure 6

Possible pathways for the nonphotochemical steps of the model reactions: (a) in-cage radical–radical coupling and (b) radical chain propagation manifold. The open-shell intermediates V and IV are generated through the photochemical activity of the enamines, as detailed in Figures 3d and 5. EWG = electron-withdrawing group. Φ = overall quantum yield of the alkylation. See ref (28) for an explanation of the quantum yield values.

Figure 7

Chain propagation manifold underlying the mechanism of the photochemical enamine-mediated enantioselective α-alkylation of butanal. (a) The initiation event, which generates the electrophilic radicals IV, is driven by the photochemical activity of the enamines (EDA complex formation or direct photoexcitation), while (b) the chain process is triggered by the radical trapping by the enamine I. (c) Two possible propagation pathways as driven either by the SET reduction of 2 or by the bromine atom transfer from 2 involving the key α-amino radical VI intermediate. (d) Evaluating the redox potential of the crucial α-aminoalkyl radical of type VI. (e) Summary of the quantum yield measurements for the three model photochemical reactions. The gray circle represents the chiral scaffold of the organic catalyst A.

Figure 8

Influence of the EDA complex formation on the amount of enamine in solution. ¹H NMR experiments were performed in CD₃CN at 298 K using a xenon lamp coupled with a monochromator and equipped with an optical fiber for the in situ illumination of the samples (λ = 470 ± 5 nm, irradiance 28.8 mW/cm²). (a) Equilibrium constant for the enamine I formation (K_enamine, measured in CD₃CN dried over 4 Å molecular sieves) and the following equilibrium to form an EDA complex, II, with 2a (K_EDA). (b) Effect on the position of equilibrium for enamine formation in the absence and the presence of the EDA acceptor 2a. (c) Effect of light illumination and the irreversible step (triggered by the photoactivity of the EDA complex II) on the concentration of enamine in solution (see Figure 3d for more details and the structures of intermediates III and V). (d) Effect of an EDA complex, unable to undergo a photoinduced irreversible SET event, on the enamine concentration. BET = back electron transfer.

Figure 9

Model reactions used for initial-rate kinetics determined by ¹H NMR analysis and the observed rate orders. (a) EDA-complex-triggered photochemical alkylation of butanal (1a) with 2,4-dinitrobenzyl bromide (2a). (b) Alkylation of 1a with diethyl bromomalonate (2c) driven by the direct photoexcitation of enamines. Reaction conditions: studies performed across a range of concentrations for each reaction component in CD₃CN, irradiation at 450 and >385 nm for 2a and 2c, respectively. The kinetic studies were repeated using in situ ¹H NMR spectroscopy (λ = 470 and 400 nm for 2a and 2c, respectively) to directly monitor the reaction progress. Both approaches gave similar kinetic profiles.

Figure 10

(a) Reaction profiles for different [2a] values showing a negative-order dependence and observed rate constants. K_obsd calculated from the slope of the plots. (b) Evolution of the catalyst concentration for the experiments in (a). We monitored the evolution of A by determining the enamine concentration in solution. (c) Overlay of plots for the kinetic data in (b) according to eq 2. Progress of the reactions followed by ¹H NMR analysis. Each point corresponds to an individual run. Reactions performed in CD₃CN under illumination by a xenon lamp with a band-pass filter at 450 nm (irradiance 4.7 mW/cm²). [1a]₀ = 1.5 M and [A]₀ = 0.1 M. Initial concentrations of 2a: 0.25 M (blue plot); 0.5 M (red plot); 1 M (green plot). The same kinetic profiles have been observed using in situ NMR monitoring of the reaction progress. See section I1 in the Supporting Information.

Figure 11

(a) Logarithmic plot according to eq 5 giving a positive fractional-order dependence on [2a] (n ≈ 0.4). (b) Kinetic data according to eq 4 for n = 0.4. For this fitting, we have used the data obtained by in situ NMR monitoring of the reaction progress, which gives the same kinetic profiles observed in Figure 10 (section I1 in the Supporting Information). This approach has the advantage of providing a larger number of data, thus allowing for a more reliable fitting. Experiments performed in NMR tubes at 298 K in CD₃CN using a monochromatic light (λ = 470 nm, irradiance 28.8 mW/cm²). [1a]₀ = 0.3 M and [A]₀ = 0.02 M. Initial concentrations of 2a: 0.05 M (blue plot); 0.1 M (red plot); 0.2 M (green plot).