A practical electrochemical oxidation of unactivated C–H bonds is presented. This reaction utilizes a simple redox mediator, quinuclidine, with inexpensive carbon and nickel electrodes to selectively functionalize “deep-seated” methylene and methine moieties. The process exhibits a broad scope and good functional group compatibility. The scalability, as illustrated by a 50 g scale oxidation of sclareolide, bodes well for immediate and widespread adoption.
C–N cross-coupling is one of the most valuable and widespread transformations in organic synthesis. Largely dominated by Pd- and Cu-based catalytic systems, it has proven to be a staple transformation for those in both academia and industry. The current study presents the development and mechanistic understanding of an electrochemically driven, Ni-catalyzed method for achieving this reaction of high strategic importance. Through a series of electrochemical, computational, kinetic, and empirical experiments, the key mechanistic features of this reaction have been unraveled, leading to a second generation set of conditions that is applicable to a broad range of aryl halides and amine nucleophiles including complex examples on oligopeptides, medicinally relevant heterocycles, natural products, and sugars. Full disclosure of the current limitations and procedures for both batch and flow scale-ups (100 g) are also described.
Olefin chemistry, through pericyclic reactions, polymerizations, oxidations, or reductions, plays an essential role in the foundation of how organic matter is manipulated.1 Despite its importance, olefin synthesis still largely relies upon chemistry invented more than three decades ago, with metathesis2 being the most recent addition. Here we describe a simple method to access olefins with any substitution pattern or geometry from one of the most ubiquitous and variegated building blocks of chemistry: alkyl carboxylic acids. The same activating principles used in amide-bond synthesis can thus be employed, under Ni- or Fe-based catalysis, to extract CO2 from a carboxylic acid and economically replace it with an organozinc-derived olefin on mole scale. Over sixty olefins across a range of substrate classes are prepared, and the ability to simplify retrosynthetic analysis is exemplified with the preparation of sixteen different natural products across a range of ten different families.
Along with amide bond formation, Suzuki cross-coupling, and reductive amination, the Buchwald–Hartwig–Ullmann-type amination of aryl halides stands as one of the most employed reactions in modern medicinal chemistry. The work herein demonstrates the potential of utilizing electrochemistry to provide a complementary avenue to access such critical bonds using an inexpensive nickel catalyst under mild reaction conditions. Of note is the scalability, functional-group tolerance, rapid rate, and the ability to employ a variety of aryl donors (Ar–Cl, Ar–Br, Ar–I, Ar–OTf), amine types (primary and secondary), and even alternative X–H donors (alcohols and amides).
Along with amide bond formation, Suzuki crosscoupling,a nd reductive amination, the Buchwald-Hartwig-Ullmann-type amination of aryl halides stands as one of the most employed reactions in modern medicinal chemistry.T he work herein demonstrates the potential of utilizing electrochemistry to provide ac omplementary avenue to access such critical bonds using an inexpensive nickel catalyst under mild reaction conditions.Ofnote is the scalability,functional-group tolerance,rapid rate,and the ability to employavariety of aryl donors (ArÀCl, ArÀBr,Ar ÀI, ArÀOTf), amine types (primary and secondary), and even alternative XÀHd onors (alcohols and amides). Scheme 2. Applicationsand extensions of the electrochemically enabled amination reaction to achieve drug modifications (A), decagram scale CÀ Ncoupling (B), amination of aryl chlorides/triflates/iodides (C), and cross-coupling using alcohol and amide as nucleophiles (D). [a] Reaction conditions: aryl bromide (3.0-5.0 equiv), amine (1.0 equiv), NiBr 2 ·glyme (10 mol %), di-tBubpy (10 mol %), DBU (2.0 equiv), DMA (0.08 m), LiBr (4.8 equiv), RVC anode, Ni cathode, constant current (I = 4mAfor 0.167 mmol scale), RT (see the SupportingInformation for experimental details). [b] Experimentalp rocedures adapted from the standard conditionsw ith modificationsi ndicated. Ford etails, see the Supporting Information.[ c] Comparisons based on specified references for each substrate (Ref. [18] and [8d]). DBU = 1,8-diaza-bicyclo[5.4.0]undec-7-ene.
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