Anodic Cyclization Reactions and the Mechanistic Strategies That Enable Optimization

Abstract

Oxidation reactions are powerful tools for synthesis because they allow us to reverse the polarity of electron-rich functional groups, generate highly reactive intermediates, and increase the functionality of molecules. For this reason, oxidation reactions have been and continue to be the subject of intense study. Central to these efforts is the development of mechanism-based strategies that allow us to think about the reactive intermediates that are frequently central to the success of the reactions and the mechanistic pathways that those intermediates trigger. For example, consider oxidative cyclization reactions that are triggered by the removal of an electron from an electron-rich olefin and lead to cyclic products that are functionalized for further elaboration. For these reactions to be successful, the radical cation intermediate must first be generated using conditions that limit its polymerization and then channeled down a productive desired pathway. Following the cyclization, a second oxidation step is necessary for product formation, after which the resulting cation must be quenched in a controlled fashion to avoid undesired elimination reactions. Problems can arise at any one or all of these steps, a fact that frequently complicates reaction optimization and can discourage the development of new transformations. Fortunately, anodic electrochemistry offers an outstanding opportunity to systematically probe the mechanism of oxidative cyclization reactions. The use of electrochemical methods allows for the generation of radical cations under neutral conditions in an environment that helps prevent polymerization of the intermediate. Once the intermediates have been generated, a series of "telltale indicators" can be used to diagnose which step in an oxidative cyclization is problematic for less successful transformation. A set of potential solutions to address each type of problem encountered has been developed. For example, problems with the initial cyclization reaction leading to either polymerization of the radical cation, elimination of a proton from or solvent trapping of that intermediate, or solvent trapping of the radical cation can be identified in the proton NMR spectrum of the crude reaction material. Such an NMR spectrum shows retention of the trapping group. The problems can be addressed by tuning the radical cation, altering the trapping group, or channeling the reactive intermediate down a radical pathway. Specific examples each are shown in this Account. Problems with the second oxidation step can be identified by poor current efficiency or general decomposition in spite of cyclic voltammetry evidence for a rapid cyclization. Solutions involve improving the oxidation conditions for the radical after cyclization by either the addition of a properly placed electron-donating group in the substrate or an increase in the concentration of electrolyte in the reaction (a change that stabilizes the cation generated from the second oxidation step). Problems with the final cation typically lead to ove...

Electrochemical C−H/N−H Activation by Water‐Tolerant Cobalt Catalysis at Room Temperature

“…[7] Despite indisputable advances,t hese C À H/N À Halkyne annulations were as of yet strongly limited to high reaction temperatures and/or stoichiometric amounts of toxic metals as the sacrificial oxidants. [6,8] In sharp contrast, we have now unraveled the power of electrochemical [9] CÀ H [10] activation [11] to enable the first cobalt-catalyzed C À H/N À Ha lkyne annulation at ambient temperature,o nw hich we report herein. Salient features of our approach comprise 1) unprecedented electrochemical CÀH/NÀHa ctivation/ annulations,2 )isoquinolone syntheses without toxic sacrificial metal oxidants,3)fully H 2 O-tolerant electrochemical CÀ Hactivation, and 4) cobalt-catalyzed CÀHfunctionalizations, under ambient conditions,e nabled by sustainable electricity (Figure 1).…”

“…[14] Ther obust cobalt catalyst was fully tolerant of H 2 O( entries 3-5), whilst the best catalytic performance was observed in as olvent mixture of MeOH and H 2 O( entries [1][2][3][4][5][6][7][8][9]. [14] Ther obust cobalt catalyst was fully tolerant of H 2 O( entries 3-5), whilst the best catalytic performance was observed in as olvent mixture of MeOH and H 2 O( entries [1][2][3][4][5][6][7][8][9].…”

Electrochemical C−H/N−H Activation by Water‐Tolerant Cobalt Catalysis at Room Temperature

“…[13] Thus,t he desired isoquinolone 3aa was obtained by means of cobalt catalysis,with NaOPiv being the optimal additive (entries 1-3). [14] Ther obust cobalt catalyst was fully tolerant of H 2 O( entries 3-5), whilst the best catalytic performance was observed in as olvent mixture of MeOH and H 2 O( entries [1][2][3][4][5][6][7][8][9]. Control experiments verified the essential role of the cobalt catalyst, the carboxylate additive,a nd the electricity (entries [10][11][12].…”

Electrooxidative Rhodium‐Catalyzed C−H/C−H Activation: Electricity as Oxidant for Cross‐Dehydrogenative Alkenylation

“…[4] Despite indisputable advances,rhodium(III)-catalyzed oxidative C À H functionalizations heavily rely on stoichiometric amounts of toxic and/or expensive copper(II) and silver(I) salts as the sacrificial oxidants. [5] In the meantime,e lectrosynthesis [6] has emerged as an increasingly viable alternative for expensive and toxic oxidants.M ajor elegant contributions in palladium catalysis were reported by the groups of Amatore/Jutand, Kakiuchi, and Mei, among others, [7] while cobalt-catalyzed electrooxidation also proved to be viable. [8] However,b oth approaches require strongly coordinating directing groups.In sharp contrast, within our program on sustainable CÀH activation, [9] we have now developed the first rhodiumcatalyzed oxidative CÀHt ransformations by means of electrooxidation ( Figure 1).…”

“…[11] Among aset of representative solvents,amixture of tAmOH and H 2 O enabled effective electrooxidative C À Ha ctivation (entries [1][2][3][4][5], even at ar educed catalyst loading (entry 6). As to the rhodium catalyst, [Cp*RhCl 2 ] 2 gave the best results (entries [5][6][7][8]. Carboxylate additives were found to be essen- tial for the CÀHa lkenylation (entries [9][10][11][12].…”