Electrochemical Nozaki-Hiyama-Kishi Coupling: Scope, Applications, and Mechanism

Abstract

One of the most oft-employed methods for C-C bond formation involving the coupling of vinyl-halides with aldehydes catalyzed by Ni and Cr (Nozaki-Hiyama-Kishi, NHK) has been rendered more practical using an electroreductive manifold. Although early studies pointed to the feasibility of such a process, those precedents were never applied by others due to cumbersome setups and limited scope. Here we show that a carefully optimized electroreductive procedure can enable a more sustainable approach to NHK, even in an asymmetric fashion on highly complex medicinally relevant systems. The e-NHK can even enable non-canonical substrate classes, such as redox-active esters, to participate with low loadings of Cr when conventional chemical techniques fail. A combination of detailed kinetics, cyclic voltammetry, and in situ UV-vis spectroelectrochemistry of these processes illuminates the subtle features of this mechanistically intricate process.

FIGURE 1.

Introduction to Nozaki–Hiyama–Kishi coupling.

FIGURE 2.

Proposed mechanism and mechanistic studies. Figure 2C middle: Comparison of the dependence of reaction rates for classical NHK (purple bars, right) and e-NHK (orange bars, left) on concentrations of 1, S11, NiCl₂·glyme, CrCl₂, Cp₂ZrCl₂, and Mn (for classical NHK) and current (for e-NHK). The designations (+) and (−) indicate a reaction carried out with an increase or decrease, respectively, in the concentration of the noted variable. Percent deviation of rate from standard conditions is given above each bar. See Supporting Information for details and complete kinetic profiles. Fig 2C bottom left: Comparison of reaction profiles for classical NHK (purple squares) with e-NHK (orange circles) for the reaction to form product 7 (see Table 1) using 0.08 M aldehyde 1 and 0.16 M vinyl bromide S11 in DMF. [NiCl₂·glyme] = 0.0016 M; [L1] = 0.0024 M; [CrCl₂] = 0.016 M; [Cp₂ZrCl₂] = 0.04 M. For classical NHK: Mn powder = 0.16 M; [LiCl] = 0.16 M. For e-NHK: [TBAB] = 0.1 M; electrodes: (+)Al/(−)Ni foam; constant current at 10 mA. Fig 2C bottom right: Comparison of reaction profiles for classical decarboxylative NHK (purple squares) with electrochemical decarboxylative NHK (orange circles) for the reaction to form product 85 (see Scheme 3) using 0.08 M aldehyde 59 and 0.08 M redox active ester 58 in DMF/THF (see Scheme 3). [CrCl₃] = 0.016 M; [TESCl] = 0.16 M. For classical NHK: Mn powder = 0.16 M. For e-NHK: [TBAClO₄] = 0.1 M; electrodes: (+)Al/(−)Ni foam; constant current at 2.5 mA. Figure 2D left: Cyclic voltammetry of the e-NHK reaction under conditions for spectroelectrochemical studies, prior to bulk electrolysis. (Black): Cr(III)-based e-NHK mixture that does not contain the Ni(II). (Teal): Cr(II)-based e-NHK. (Plum): Cr(III)-based e-NHK. All experiments contain [Cr] = 0.016 M, [NiCl₂·glyme] = 0.0016 M, [L4] = 0.0024 M, [Cp₂ZrCl₂] = 0.04 M, [1] = 0.08 M, [S11] = 0.16 M, [TBAPF₆] = 0.1 M, DMF, a Ni working electrode, an Al counter electrode. CV data acquired with 0.025 V/s scan rate. Figure 2D right: CrCl₃·3THF: [CrCl₃·3THF] = 2 mM. CrCl₃·3THF+ Ni(II) catalyst: [CrCl₃·3THF] = 2 mM, [NiCl₂·glyme] = 0.2 mM, [L4] = 0.3 mM. Ni(II) catalyst: [NiCl₂·glyme] = 0.2 mM, [L4] = 0.3 mM. All CV experiments were run in DMF with [TBAPF₆] = 0.1 M and acquired with a scan rate of 100 mV/s, GC working electrode, and Al counter electrode. All potentials referenced to Fc^+/0. Figure 2E left. [S11] = 160 mM, [1] = 80 mM, [CrCl₂] = 16 mM, [Cp₂ZrCl₂] = 40 mM, [NiCl₂·glyme] = 1.6 mM, [L4] = 2.4 mM (teal), [S11] = 160 mM, [1] = 80 mM, [CrCl₃·3THF] = 16 mM, [Cp₂ZrCl₂] = 40 mM, [NiCl₂·glyme] = 1.6 mM, [L4] = 2.4 mM (plum), [S11] = 160 mM, [1] = 80 mM, [CrCl₃·3THF] = 16 mM, [Cp₂ZrCl₂] = 40 mM, [NiCl₂·glyme] = 0 mM, [L4] = 0 mM (tangerine), and [CrCl₃·3THF] = 16 mM (clover). Figure 2E right: UV-Vis of: Cr(II)-based e-NHK mixture prior to bulk electrolysis (solid teal), Cr(II)-based e-NHK mixture after an applied potential of −1.5 V vs Fc^+/0 for 15 minutes and then an applied potential −2.0 V vs Fc^+/0 for 30 minutes (dashed teal), Cr(III)-based e-NHK mixture prior to bulk electrolysis (solid plum), Cr(III) based e-NHK mixture after an applied potential of −1.5 V vs Fc^+/0 for 15 minutes and then an applied potential −2.0 V vs Fc^+/0 for 30 minutes (dashed plum). Absorbance data were baseline-corrected by taking the absorbance at 900 nm to be zero. *indicates portions of the UV-vis absorbance data that have signal saturation inherent to the detector/light source used for these experiments. Figure 2F middle left: Comparison of induction period with different current. [58] = 0.08 M, [59] = 0.08 M, [CrCl₃] = 0.016 M, [TESCl] = 0.16 M, [TBAClO₄] = 0.1 M, with 2.5 mA, 5 mA and 7.5 mA, respectively. Figure 2F middle right: reaction rate after removing induction period. Figure 2F bottom left: Comparison of the dependence of reaction rates on concentration of 58, 59, and CrCl₃.

SCHEME 1.. Enantioselective version of the e-NHK coupling.

^aUsed for both Cr-complex formation and electrochemical reaction. ^bYields determined by crude ¹H NMR using CH₂Br₂ as the internal standard; er determined by Mosher ester analysis. ^cNot determined. ^dDIPEA was used for Cr-complex formation instead of proton sponge. ^eCH₃CN was used for Cr-complex formation; DMF/CH₃CN (4:1 v/v). ^fer reported by Kishi et al. using stoichiometric CrCl₂–L* complex.

SCHEME 2.. Applications of the e-NHK coupling.

Yields of isolated products are indicated in each case. See SI for reaction conditions. (A to E) Application of the e-enantioselective NHK to five real-world examples including some that are relevant to the synthesis of Halaven.

SCHEME 3.. E-decarboxylative NHK coupling.

^a0.2 mmol; yields determined by crude ¹H NMR using 1,3,5-trimethoxybenzene as the internal standard. ^bIsolated after desilylation (TBAF, THF) of the crude mixture. ^cIsolated as corresponding triethylsilyl ether.