Regioselective aliphatic C-H functionalization using frustrated radical pairs.

Frustrated Lewis pairs (FLPs) are well documented for the activation of small molecules such as dihydrogen and carbon dioxide1-4. Although canonical FLP chemistry is heterolytic in nature, recent work has shown that certain FLPs can undergo single-electron transfer to afford radical pairs5. Owing to steric encumbrance and/or weak bonding association, these radicals do not annihilate one another, and they have thus been named frustrated radical pairs (FRPs). Notable preliminary results suggest that FRPs may be useful reagents in chemical synthesis6-8, although their applications remain limited. Here we demonstrate that the functionalization of C(sp3)-H bonds can be accomplished using a class of FRPs generated from disilazide donors and an N-oxoammonium acceptor. Together, these species undergo single-electron transfer to generate a transient and persistent radical pair capable of cleaving unactivated C-H bonds to furnish aminoxylated products. By tuning the structure of the donor, it is possible to control regioselectivity and tailor reactivity towards tertiary, secondary or primary C-H bonds. Mechanistic studies lend strong support for the formation and involvement of radical pairs in the target reaction.

Accessing Alkoxy Radicals via Frustrated Radical Pairs: Diverse Oxidative Functionalizations of Tertiary Alcohols.

Alkoxy radicals are versatile reactive intermediates in organic synthesis. Here, we leverage the principle of frustrated radical pair to provide convenient access to these highly reactive species directly from tertiary alcohols via oxoammonium-mediated oxidation of the corresponding alkoxides. This approach enabled various synthetically useful transformations including ß-scission, radical cyclization, and remote C-H functionalization, giving rise to versatile alkoxyamines that can be further elaborated to various functionalities.

Frustrated Radical Pairs in Organic Synthesis.

Frustrated radical pairs (FRPs) describe the phenomenon that two distinct radicals─which would otherwise annihilate each other to form a closed-shell covalent adduct─can coexist in solution, owing to steric repulsion or weak bonding association. FRPs are typically formed via spontaneous single-electron transfer between two sterically encumbered precursors─an oxidant and a reductant─under ambient conditions. The two components of a FRP exhibit orthogonal chemical properties and can often act in cooperativity to achieve interesting radical reactivities. Initially observed in the study of traditional frustrated Lewis pairs, FRPs have recently been shown to be capable of homolytically activating various chemical bonds. In this Perspective, we will discuss the discovery of FRPs, their fundamental reactivity in chemical bond activation, and recent developments of their use in synthetic organic chemistry, including in C-H bond functionalization. We anticipate that FRPs will provide new reaction strategies for solving challenging problems in modern organic synthesis.

Silver-Catalyzed Enantioselective Propargylic C-H Bond Amination through Rational Ligand Design.

Asymmetric C-H amination via nitrene transfer is a powerful tool to prepare enantioenriched amine precursors from abundant C-H bonds. Herein, we report a regio- and enantioselective synthesis of γ-alkynyl γ-aminoalcohols via a silver-catalyzed propargylic C-H amination. The protocol was enabled by a new bis(oxazoline) (BOX) ligand designed via a rapid structure-activity relationship (SAR) analysis. The method utilizes accessible carbamate esters bearing γ-propargylic C-H bonds and furnishes versatile products in good yields and excellent enantioselectivity (90-99% ee). The putative Ag-nitrene is proposed to undergo enantiodetermining hydrogen-atom transfer (HAT) during the C-H amination event. Density functional theory calculations shed insight into the origin of enantioselectivity in the HAT step.

Chemo- and Enantioselective Intramolecular Silver-Catalyzed Aziridinations.

Asymmetric nitrene-transfer reactions are a powerful tool for the preparation of enantioenriched amine building blocks. Reported herein are chemo- and enantioselective silver-catalyzed aminations which transform di- and trisubstituted homoallylic carbamates into [4.1.0]-carbamate-tethered aziridines in good yields and with ee values of up to 92 %. The effects of the substrate, silver counteranion, ligand, solvent, and temperature on both the chemoselectivity and ee value were explored. Stereochemical models were proposed to rationalize the observed absolute stereochemistry of the aziridines, which undergo nucleophilic ring opening to yield enantioenriched amines with no erosion in stereochemical integrity.

Nitrene transfer catalysts for enantioselective C-N bond formation.

Transition-metal-catalysed, non-enzymatic transformations of C-H and C=C bonds to C-N bonds through nitrene transfer (NT) are powerful synthetic tools to prepare valuable amine building blocks. Although the first examples of racemic NT were reported more than 50 years ago, catalysts that mediate enantioselective NT with a broad substrate scope have been slow to emerge. However, the past ten years have seen the discovery of several first-row, second-row and third-row transition metal catalysts for asymmetric NT. This Review covers recent developments in asymmetric aziridination and C-H bond amination reactions. We describe catalyst design principles, re-evaluate traditional catalyst architectures, show how the scope of nitrene precursors has expanded and present new mechanistic insights. Following this, we highlight remaining opportunities and challenges to developing more practical and general synthetic methodologies. Realizing chemoselective, site-selective and enantioselective intermolecular NT will streamline amine synthesis and allow us to explore new chemical space.

Sequential Reduction of Nitroalkanes Mediated by CS2 and Amidine/Guanidine Bases: A Controllable Nef Reaction.

In this letter, we describe a mild, functional group-tolerant reductive Nef reaction that utilizes CS2 and an amidine or guanidine base to sequentially cleave N-O bonds. These conditions transform secondary nitroalkanes to ketones via an isolable oxime with minimal erosion at labile stereogenic carbons, show excellent compatibility with groups sensitive to oxidizing or reducing conditions, display good scalability, and are well-suited for generating useful 3-pyrrolidinone motifs from readily accessible 1,3-dipolar cycloaddition products.