Photochemical C-H Activation Enables Nickel-Catalyzed Olefin Dicarbofunctionalization

Abstract

Alkenes, ethers, and alcohols account for a significant percentage of bulk reagents available to the chemistry community. The petrochemical, pharmaceutical, and agrochemical industries each consume gigagrams of these materials as fuels and solvents each year. However, the utilization of such materials as building blocks for the construction of complex small molecules is limited by the necessity of prefunctionalization to achieve chemoselective reactivity. Herein, we report the implementation of efficient, sustainable, diaryl ketone hydrogen-atom transfer (HAT) catalysis to activate native C-H bonds for multicomponent dicarbofunctionalization of alkenes. The ability to forge new carbon-carbon bonds between reagents typically viewed as commodity solvents provides a new, more atom-economic outlook for organic synthesis. Through detailed experimental and computational investigation, the critical effect of hydrogen bonding on the reactivity of this transformation was uncovered.

Figure 1.

Proposed mechanism for three-component HAT-mediated photoredox/nickel dual-catalyzed DCF of alkenes. BDE were calculated at the (U)B3LYP-D3/def2-TZVPP//(U)B3LYP-D3/def2-SVP level of theory.

Figure 2.

Computational analysis of the divergent reactivity of alkyl radical in the isopropyl alcohol system. Electronic (in parentheses), enthalpy (in bracket), and free energies (kcal/mol; 298 K) given were calculated at the (U)B3LYP-D3/def2-TZVPP-CPCM(benzene)//(U)B3LYP-D3/def2-SVP-CPCM(benzene) (black) and DLPNO–CCSD(T)/def2-TZVPP//(U)B3LYP-D3/def2-SVP-CPCM(benzene) (blue) levels of method.

Figure 3.

Selectivities of various secondary radicals for competing DCF and CC pathways. (A) Values indicate ratio of DCF to CC product determined by crude ¹H NMR. Reaction conditions: 4-bromobenzonitrile (1 equiv, 0.1 mmol), tert-butyl acrylate or acrylonitrile (2 equiv or 4 equiv, 0.2 or 0.4 mmol), C–H precursor (15 equiv, 1.5 mmol), Ni 2 (10 mol %, 0.01 mmol), benzophenone 1 (20 mol %, 0.02 mmol), K₂HPO₄ (2 equiv, 0.2 mmol), TFT (0.1 M), 24 h, irradiating with 390 nm Kessil lamp. (B) NCI plots and the computed energetics (free energy, kcal/mol) of the Giese addition transition states of various alkyl radicals to acrylate. (C) Proposed hydrogen bonding increases the rate of Giese-type addition vs direct metalation in the reaction of secondary ethoxy radical. Free energies (kcal/mol; 298 K) given were calculated at the DLPNO–CCSD(T)/def2-TZVPP//(U)B3LYP-D3/def2-SVP-CPCM(benzene) level of method.

Figure 4.

Competition reactions and related computational details. (A) Hydroalkylation competition reactions, alkenes (1 equiv each, 0.1 mmol), C–H precursor (15 equiv, 1.5 mmol), Ni 2 (10 mol %, 0.01 mmol), benzophenone 1 (20 mol %, 0.02 mmol), TFT (0.1 M), irradiating with 390 nm Kessil lamp for 30–90 min, reactions carried out to ~25% conversion. (B) DCF competition reactions, standard reaction conditions as in Table 1. (C) Computed energetics for the Giese addition processes. Free energies (kcal/mol; 298 K) given were calculated at the DLPNO–CCSD(T)/def2-TZVPP//(U)B3LYP-D3/def2-SVP-CPCM (benzene) level of method. (D) Result of reaction of i-PrOH/acrylonitrile/p-BrC₆H₄CN under standard reaction conditions.

Figure 5.

Experiments with 1-cyclopropylethanol as C–H precursor. (A) DCF reactions with 1-cyclopropylethanol; standard reaction conditions as in Table 1. (B) Proposed pathway of the formation of cyclopentane-containing DCF product. (C) Computational analysis of the competing ring-opening and Giese addition of tertiary radical in acrylate and acrylonitrile systems. Electronic (in parentheses), enthalpy (in bracket), and free energies (kcal/mol; 298 K) given were calculated at the (U)B3LYP-D3/def2-TZVPP-CPCM(benzene)//(U)B3LYP-D3/def2-SVP-CPCM-(benzene) (black) and DLPNO–CCSD(T)/def2-TZVPP//(U)B3LYP-D3/def2-SVP-CPCM(benzene) (blue) levels of method.