Benzylic C(sp3)-H fluorination.

The selective fluorination of C(sp3)-H bonds is an attractive target, particularly for pharmaceutical and agrochemical applications. Consequently, over recent years much attention has been focused on C(sp3)-H fluorination, and several methods that are selective for benzylic C-H bonds have been reported. These protocols operate via several distinct mechanistic pathways and involve a variety of fluorine sources with distinct reactivity profiles. This review aims to give context to these transformations and strategies, highlighting the different tactics to achieve fluorination of benzylic C-H bonds.

Diastereodivergent nucleophile-nucleophile alkene chlorofluorination.

The selective hetero-dihalogenation of alkenes provides useful building blocks for a broad range of chemical applications. Unlike homo-dihalogenation, selective hetero-dihalogenation reactions, especially fluorohalogenation, are underdeveloped. Current approaches combine an electrophilic halogen source with a nucleophilic halogen source, which necessarily leads to anti-addition, and regioselectivity has only been achieved using highly activated alkenes. Here we describe an alternative, nucleophile-nucleophile approach that adds chloride and fluoride ions over unactivated alkenes in a highly regio-, chemo- and diastereoselective manner. A curious switch in the reaction mechanism was discovered, which triggers a complete reversal of the diastereoselectivity to promote either anti- or syn-addition. The conditions are demonstrated on an array of pharmaceutically relevant compounds, and detailed mechanistic studies reveal the selectivity and the switch between the syn- and anti-diastereomers are based on different active iodanes and which of the two halides adds first.

Bromide-Mediated Silane Oxidation: A Practical Counter-Electrode Process for Nonaqueous Deep Reductive Electrosynthesis.

The counter-electrode process of an organic electrochemical reaction is integral for the success and sustainability of the process. Unlike for oxidation reactions, counter-electrode processes for reduction reactions remain limited, especially for deep reductions that apply very negative potentials. Herein, we report the development of a bromide-mediated silane oxidation counter-electrode process for nonaqueous electrochemical reduction reactions in undivided cells. The system is found to be suitable for replacing either sacrificial anodes or a divided cell in several reported reactions. The conditions are metal-free, use inexpensive reagents and a graphite anode, are scalable, and the byproducts are reductively stable and readily removed. We showcase the translation of a previously reported divided cell reaction to a >100 g scale in continuous flow.

Silver-Catalyzed (Z)-ß-Fluoro-vinyl Iodonium Salts from Alkynes: Efficient and Selective Syntheses of Z-Monofluoroalkenes.

Monofluoroalkenes are stable and lipophilic amide bioisosteres used in medicinal chemistry. However, efficient and stereoselective methods for synthesizing Z-monofluoroalkenes are underdeveloped. We envisage (Z)-ß-fluoro-vinyl iodonium salts (Z-FVIs) as coupling partners for the diverse and stereoselective synthesis of Z-monofluoroalkenes. Disclosed herein is the development and application of a silver(I)-catalyzed process for accessing a broad scope of (Z)-FVIs with exclusive Z-stereoselectivity and regioselectivity from alkynes in a single step. Experimental and computational studies provide insight into the mechanism of the catalytic cycle and the role of the silver(I) catalyst, and the reactivity of (Z)-FVIs is explored through several stereospecific derivatizations.

Alkene 1,3-Difluorination via Transient Oxonium Intermediates.

The 1,3-difunctionalization of unactivated alkenes is an under-explored transformation that leads to moieties that are otherwise challenging to prepare. Herein, we report a hypervalent iodine-mediated 1,3-difluorination of homoallylic (aryl) ethers to give unreported 1,3-difluoro-4-oxy groups with moderate to excellent diastereoselectivity. The transformation proceeds through a different mode of reactivity for 1,3-difunctionalization, in which a regioselective addition of fluoride opens a transiently formed oxonium intermediate to rearrange an alkyl chain. The optimized protocol is scalable and shown to proceed well with a variety of functional groups and substitution on the alkenyl chain, hence providing ready access to this fluorinated, conformationally controlled moiety.

A Stoichiometric Haloform Coupling for Ester Synthesis with Secondary Alcohols.

The haloform reaction from methyl ketones to carboxylic acids is one of the oldest known synthetic organic reactions, which has been used in myriad applications over the decades. The corresponding reaction to produce esters is, however, less developed, as the reaction is generally limited to simple, primary alcohols that are used in solvent-level quantities, thereby restricting the complexity of esters that can be directly formed. Herein, we detail the development of a general ester-forming haloform coupling reaction using one equivalent of alcohol. Mechanistic and kinetic modelling studies demonstrated that the key intermediates are formed under equilibrium, which facilitated the development of conditions that are amenable to secondary alcohols.

Pulsed electrolysis: enhancing primary benzylic C(sp3)-H nucleophilic fluorination.

Electrosynthesis is an efficient and powerful tool for the generation of elusive reactive intermediates. The application of alternative electrolysis waveforms provides a new level of control for dynamic redox environments. Herein, we demonstrate that pulsed electrolysis provides a favourable environment for the generation and fluorination of highly unstable primary benzylic cations from C(sp3)-H bonds. By introduction of a toff period, we propose this waveform modulates the electrical double layer to improve mass transport and limit over-oxidation.

Electrochemical Benzylic C(sp3)-H Direct Amidation.

Amide bonds are ubiquitous and found in a myriad of functional molecules. Although formed in a reliable and robust fashion, alternative amide bond disconnections provide flexibility and synthetic control. Herein we describe an electrochemical method to form the non-amide C-N bond from direct benzylic C(sp3)-H amidation. Our approach is applied toward the synthesis of secondary amides by coupling secondary benzylic substrates with substituted primary benzamides. The reaction has been scaled up to a multigram scale in flow.

Electrochemical synthesis of biaryls by reductive extrusion from N,N'-diarylureas.

The synthesis of biaryl compounds by the transition-metal free coupling of arenes is an important contemporary challenge, aiming to avoid the toxicity and cost profiles associated with the metal catalysts commonly used in the synthesis of these pharmaceutically relevant motifs. In this paper, we describe an electrochemical approach to the synthesis of biaryls in which aniline derivatives are coupled through the formation and reduction of a temporary urea linkage. The conformational alignment of the arenes in the N,N'-diaryl urea intermediates promotes C-C bond formation following single-electron reduction. Our optimized conditions are suitable for the synthesis of a variety of biaryls, including sterically hindered examples carrying ortho-substituents, representing complementary reactivity to most metal catalysed methods.

Electrochemical Benzylic C(sp3)-H Acyloxylation.

The development of sustainable C(sp3)-H functionalization methods is of great interest to the pharmaceutical and agrochemical industries. Anodic oxidation is an efficient means of producing benzylic cations that can undergo subsequent in situ nucleophilic attack to afford functionalized benzylic products. Herein, we demonstrate the suitability of carboxylic acids as nucleophiles to yield benzylic esters. This method employs a series of secondary benzylic substrates and functionalized carboxylic acids and is demonstrated on a gram scale in flow.

Intramolecular Alkene Fluoroarylation of Phenolic Ethers Enabled by Electrochemically Generated Iodane.

The 3-substituted chromane core is found in several bioactive natural products. Herein, we describe a route to 3-fluorinated chromanes from allylic phenol ethers. Our external oxidant-free approach takes advantage of an electrochemical generation of a hypervalent iodine species, difluoro-λ3-tolyl iodane, which mediates the alkene fluoroarylation. High yields and selectivity for this transformation are achieved for electron poor substrates. The redox chemistry has been characterized for the electrochemical generation of the iodane in the presence of fluoride, and insights into the mechanism are given. The transformation has been demonstrated on gram scales, which indicates the potential broader utility of the process.

Direct electrochemical hydrodefluorination of trifluoromethylketones enabled by non-protic conditions.

CF2H groups are unique due to the combination of their lipophilic and hydrogen bonding properties. The strength of H-bonding is determined by the group to which it is appended. Several functional groups have been explored in this context including O, S, SO and SO2 to tune the intermolecular interaction. Difluoromethyl ketones are under-studied in this context, without a broadly accessible method for their preparation. Herein, we describe the development of an electrochemical hydrodefluorination of readily accessible trifluoromethylketones. The single-step reaction at deeply reductive potentials is uniquely amenable to challenging electron-rich substrates and reductively sensitive functionality. Key to this success is the use of non-protic conditions enabled by an ammonium salt that serves as a reductively stable, masked proton source. Analysis of their H-bonding has revealed difluoromethyl ketones to be potentially highly useful dual H-bond donor/acceptor moieties.

Dichloromeldrum's Acid (DiCMA): A Practical and Green Amine Dichloroacetylation Reagent.

Dichloromeldrum's acid is introduced as a bench-stable, nonvolatile reagent for the dichloroacetylation of anilines and alkyl amines to produce α,α-dichloroacetamides, which are important motifs for medicinal chemistry. Products are formed in good to excellent yields with reagent grade solvents, and, as the only byproducts are acetone and CO2, no column chromatography is required. Thus, this reagent is practical, efficient, and green for the dichloroacetylation of primary amines.

Synthesis, Stability, and Biological Studies of Fluorinated Analogues of Thromboxane A2.

Platelet activation results in the generation of thromboxane A2 (TxA2), which promotes thrombus formation by further amplifying platelet function, as well as causing vasoconstriction. Due to its role in thrombus formation and cardiovascular disease, its production is the target of antiplatelet drugs such as aspirin. However, the study of TxA2-stimulated cellular function has been limited by its instability (t 1/2 = 32 s, pH = 7.4). Although more stable analogues such as U46619 and difluorinated 10,10-F2-TxA2 have been prepared, we targeted a closer mimic to TxA2 itself, monofluorinated 10-F-TxA2, since the number of fluorine atoms can affect function. Key steps in the synthesis of F-TxA2 included α-fluorination of a lactone bearing a ß-alkoxy group, and a novel synthesis of the strained acetal. F-TxA2 was found to be 105 more stable than TxA2, and surprisingly was only slightly less stable than F2-TxA2. Preliminary biological studies showed that F-TxA2 has similar potency as TxA2 toward inducing platelet aggregation but was superior to F2-TxA2 in activating integrin αIIbß3.

Electrode Materials in Modern Organic Electrochemistry.

The choice of electrode material is critical for achieving optimal yields and selectivity in synthetic organic electrochemistry. The material imparts significant influence on the kinetics and thermodynamics of electron transfer, and frequently defines the success or failure of a transformation. Electrode processes are complex and so the choice of a material is often empirical and the underlying mechanisms and rationale for success are unknown. In this review, we aim to highlight recent instances of electrode choice where rationale is offered, which should aid future reaction development.

Electrochemical Vicinal Difluorination of Alkenes: Scalable and Amenable to Electron-Rich Substrates.

Fluorinated alkyl groups are important motifs in bioactive compounds, positively influencing pharmacokinetics, potency and conformation. The oxidative difluorination of alkenes represents an important strategy for their preparation, yet current methods are limited in their alkene-types and tolerance of electron-rich, readily oxidized functionalities, as well as in their safety and scalability. Herein, we report a method for the difluorination of a number of unactivated alkene-types that is tolerant of electron-rich functionality, giving products that are otherwise unattainable. Key to success is the electrochemical generation of a hypervalent iodine mediator using an "ex-cell" approach, which avoids oxidative substrate decomposition. The more sustainable conditions give good to excellent yields in up to decagram scales.

Meisenheimer Complexes in SN Ar Reactions: Intermediates or Transition States?

Meisenheimer's missing! Anionic σ-complexes, best known as Meisenheimer complexes, have long been assumed to be intermediates in SN Ar reactions. New evidence now suggests that these intermediates may only be formed in select cases and that a concerted pathway is more common. These claims are supported by 12 C/13 C kinetic isotopes effects, determined using a new method based on 19 F NMR, and DFT calculations.

Electrochemical Aminoxyl-Mediated α-Cyanation of Secondary Piperidines for Pharmaceutical Building Block Diversification.

Secondary piperidines are ideal pharmaceutical building blocks owing to the prevalence of piperidines in commercial drugs. Here, we report an electrochemical method for cyanation of the heterocycle adjacent to nitrogen without requiring protection or substitution of the N-H bond. The reaction utilizes ABNO (9-azabicyclononane N-oxyl) as a catalytic mediator. Electrochemical oxidation of ABNO generates the corresponding oxoammonium species, which promotes dehydrogenation of the 2° piperidine to the cyclic imine, followed by addition of cyanide. The low-potential, mediated electrolysis process is compatible with a wide range of heterocyclic and oxidatively sensitive substituents on the piperidine ring and enables synthesis of unnatural amino acids.