Site-Selective C–H Functionalization via Synergistic Use of Electrochemistry and Transition Metal Catalysis

Abstract

Conspectus Electrochemical synthesis of organic compounds has emerged as an attractive and environmentally benign alternative to conventional approaches for oxidation and reduction of organic compounds that utilizes electric current instead of chemical oxidants and reductants. As such, many useful transformations have been developed, including the Kolbe reaction, the Simons fluorination process, the Monsanto adiponitrile process, and the Shono oxidation, to name a few. Electrochemical C–H functionalization represents one of the most promising reaction types among many electrochemical transformations, since this process avoids prefunctionalization of substrates and provides novel retrosynthetic disconnections. However, site-selective anodic oxidation of C–H bonds is still a fundamental challenge due to the high oxidation potentials of C–H bonds compared to organic solvents and common functional groups. To overcome this issue, indirect electrolysis via the action of a mediator (a redox catalyst) is regularly employed, by which the selectivity can be controlled following reaction of said mediator with the substrate. Since the redox potentials of transition metal complexes can be easily tuned by modification of the ligand, the synergistic use of electrochemistry and transition metal catalysis to achieve site-selective C–H functionalization is an attractive strategy. In this Account, we summarize and contextualize our recent efforts toward transition metal-catalyzed electrochemical C–H functionalization proximal to a suitable directing group. We have developed C–H oxygenation, acylation, alkylation, and halogenation reactions in which a Pd­(II) species is oxidized to a Pd­(III) or Pd­(IV) intermediate by anodic oxidation, followed by reductive elimination to form the corresponding C–O, C–C, and C–X bonds. Importantly, improved monofunctionalization selectivity is achieved in the Pd-catalyzed C­(sp3)–H oxygenation compared to conventional approaches using PhI­(OAc)2 as the chemical oxidant. Physical separators are sometimes used to prevent the electrochemical deposition of Pd black on the cathode resulting from reduction of high valent Pd species. We skirted this issue through the development a Cu-catalyzed electrochemical C­(sp2)–H amination using n-Bu4NI as a redox cocatalyst in an undivided cell. In addition, we developed Ir-catalyzed electrochemical vinylic C–H functionalization of acrylic acids with alkynes in an undivided cell, affording various substituted α-pyrones in good to excellent yield. More importantly, chemical oxidants, including Ag2CO3, Cu­(OAc)2, and PhI­(OAc)2, resulted in much lower yields in the absence of electrical current under otherwise identical conditions. As elaborated below, progress in the area of electrochemical transition metal-catalyzed synthesis provides an effective platform for environmentally friendly and sustainable selective chemical transformations.

Making electrochemistry easily accessible to the synthetic chemist

“…The advantages of the setup employed will be discussed for each type of reaction. See the following reviews for specific transformations: cross coupling, [24][25][26] CH activation, [27][28][29][30][31][32][33][34][35][36] asymmetric synthesis, 14 heterocycle formation, [37][38][39] arylation, 40 fluorination, 41 organometallic catalysis, 42,43 cation pool method. 44 The different types of reactions can be summarised as: (1) direct electrochemical reaction with solvent degradation as counter reaction, (2) direct electrochemical reaction with nonsolvent degradation as counter reaction, (3) mediated or catalysed electrochemical reaction, (4) redox combined electrochemical reaction (Fig.…”

“…This tutorial review provides an introduction to electrochemistry and is not designed to be an extensive review of all synthetic electrochemical examples. For further information recent reviews and the references therein are recommended: certain transformations including cross coupling, [24][25][26] CH activation, [27][28][29][30][31][32][33][34][35][36] asymmetric synthesis, 14 heterocycle formation, [37][38][39] arylation, 40 fluorination, 41 organometallic catalysis, 42,43 cation pool method, 44 continuous reactor types, [45][46][47][48][49][50][51][52][53][54][55] analytical tools 56,57 and general reviews and perspectives. [1][2][3][4][5][6][7][8][9][10][11][12][13]…”

Oxoiron(v) mediated selective electrochemical oxygenation of unactivated C–H and CC bonds using water as the oxygen source

“…Electrochemical oxidation presents an attractive alternative to traditional chemical reagents for large-scale applications, mostly owing to the generation of less toxic waste than that produced by current chemical processes. [1][2][3][4] However, electrochemical oxidation of unactivated C-H bonds, the most ubiquitous structural motifs in complex natural products, remains a signicant challenge. The difficulty in such oxidation is the high redox potentials required to oxidize such moieties by direct electrolysis (frequently above 3.0 V vs. SCE, which is signicantly higher than the thermodynamic potential).…”

Nickela‐electrocatalyzed Mild C−H Alkylations at Room Temperature

“…Recently electrosynthesis [15] has gained considerable momentum due to the use of electricity as a sustainable alternative for toxic chemical redox equivalents, thereby avoiding stoichiometric formation of waste products. In this regard, electrochemical CÀH activation [16] has resulted in a renaissance in this field with notable contributions by Mei, [17] Ackermann, [18] Lei, [19] and Xu. [20] Despite the undisputable advances in metalla-electrooxidative C À H activation, net redox-neutral transformations under electrochemical conditions have barely been explored, while the effect of electricity was shown to be beneficial for net redox-neutral nickel-catalyzed Ullmann-type CÀN bondforming reactions.…”