Couple-close construction of polycyclic rings from diradicals.

Heteroarenes are ubiquitous motifs in bioactive molecules, conferring favourable physical properties when compared to their arene counterparts1-3. In particular, semisaturated heteroarenes possess attractive solubility properties and a higher fraction of sp3 carbons, which can improve binding affinity and specificity. However, these desirable structures remain rare owing to limitations in current synthetic methods4-6. Indeed, semisaturated heterocycles are laboriously prepared by means of non-modular fit-for-purpose syntheses, which decrease throughput, limit chemical diversity and preclude their inclusion in many hit-to-lead campaigns7-10. Herein, we describe a more intuitive and modular couple-close approach to build semisaturated ring systems from dual radical precursors. This platform merges metallaphotoredox C(sp2)-C(sp3) cross-coupling with intramolecular Minisci-type radical cyclization to fuse abundant heteroaryl halides with simple bifunctional feedstocks, which serve as the diradical synthons, to rapidly assemble a variety of spirocyclic, bridged and substituted saturated ring types that would be extremely difficult to make by conventional methods. The broad availability of the requisite feedstock materials allows sampling of regions of underexplored chemical space. Reagent-controlled radical generation leads to a highly regioselective and stereospecific annulation that can be used for the late-stage functionalization of pharmaceutical scaffolds, replacing lengthy de novo syntheses.

Direct Deaminative Functionalization.

Selective functional group interconversions in complex molecular settings underpin many of the challenges facing modern organic synthesis. Currently, a privileged subset of functional groups dominates this landscape, while others, despite their abundance, are sorely underdeveloped. Amines epitomize this dichotomy; they are abundant but otherwise intransigent toward direct interconversion. Here, we report an approach that enables the direct conversion of amines to bromides, chlorides, iodides, phosphates, thioethers, and alcohols, the heart of which is a deaminative carbon-centered radical formation process using an anomeric amide reagent. Experimental and computational mechanistic studies demonstrate that successful deaminative functionalization relies not only on outcompeting the H-atom transfer to the incipient radical but also on the generation of polarity-matched, productive chain-carrying radicals that continue to react efficiently. The overall implications of this technology for interconverting amine libraries were evaluated via high-throughput parallel synthesis and applied in the development of one-pot diversification protocols.

Bicyclobutanes: from curiosities to versatile reagents and covalent warheads.

The unique chemistry of small, strained carbocyclic systems has long captivated organic chemists from a theoretical and fundamental standpoint. A resurgence of interest in strained carbocyclic species has been prompted by their potential as bioisosteres, high fraction of sp3 carbons, and limited appearance in the patent literature. Among strained ring systems, bicyclo[1.1.0]butane (BCB) stands apart as the smallest bicyclic carbocycle and is amongst the most strained carbocycles known. Despite the fact that BCBs have been synthesized and studied for well over 50 years, they have long been regarded as laboratory curiosities. However, new approaches for preparing, functionalizing, and using BCBs in "strain-release" transformations have positioned BCBs to be powerful synthetic workhorses. Further, the olefinic character of the bridgehead bond enables BCBs to be elaborated into various other ring systems and function as covalent warheads for bioconjugation. This review will discuss the recent developments in the synthesis and functionalization of BCBs as well as the applications of these strained rings in synthesis and drug discovery. An overview of the properties and the historical context of this interesting structure will be provided.

Radical-Polar Crossover Annulation: A Platform for Accessing Polycyclic Cyclopropanes.

Photoredox-mediated radical/polar crossover (RPC) processes provide unique solutions to challenging annulations. Herein, we describe an approach to the cyclopropanation of olefins that are embedded within bicyclic scaffolds. Whereas these systems are notoriously recalcitrant toward classical cyclopropanation approaches, RPC cyclopropanation can be executed with ease, leading to polycarbocyclic and polyheterocyclic cyclopropanes. The cyclopropanation proceeds through a photoredox-enabled Giese-type radical addition followed by an intramolecular anionic substitution reaction on a neopentyl leaving group.

Late stage C-H functionalization via chalcogen and pnictogen salts.

Late-stage functionalization (LSF) of heteroarenes can dramatically accelerate SAR studies by enabling the installation of functional groups that would otherwise complicate a synthetic sequence. Although heteroaryl halides and boronic esters have well-established chemistries for LSF, alternatives that enable site-selective C-H functionalization are highly attractive. Recently, three unrelated cationic groups (phosphonium, pyridinium, and thianthrenium), which can replace C-H bonds late stage, have been identified as precursors to various functional groups. This review will discuss the synthesis and application of these three salts with an emphasis on their use for LSF and application to medicinal chemistry.

Three-Component Olefin Dicarbofunctionalization Enabled by Nickel/Photoredox Dual Catalysis.

An intermolecular, photocatalytic dicarbofunctionalization (DCF) of olefins enabled by the merger of Giese-type addition with Ni/photoredox dual catalysis has been realized. Capitalizing on the rapid addition of 3° radicals to alkenes and their reluctance toward single electron metalation to Ni complexes, regioselective alkylation and arylation of olefins is possible. This dual catalytic method not only permits elaborate species to be assembled from commodity materials, but also allows quaternary and tertiary centers to be installed in a singular, chemoselective olefin difunctionalization. This multicomponent process occurs under exceptionally mild conditions, compatible with a diverse range of functional groups and synthetic handles such as pinacolboronate esters. This technology was directly applied to the synthesis of an intermediate to a preclinical candidate (TK-666) and its derivatives.

Photoredox Radical/Polar Crossover Enables Construction of Saturated Nitrogen Heterocycles.

Photoredox-mediated radical/polar crossover (RPC) processes offer new avenues for the synthesis of cyclic molecules. This process has been realized for the construction of medium-sized saturated nitrogen heterocycles. Photocatalytically generated alkyl radicals possessing pendant leaving groups engage imines in C-C bond formation, and subsequent reduction of the intermediate nitrogen-centered radical triggers anionic ring closure. With the aid of visible light irradiation, substituted pyrrolidines, piperidines, and azepanes can be prepared under mild, redox-neutral conditions.

Photoredox Catalysis Enables Access to N-Functionalized 2,1-Borazaronaphthalenes.

The synthesis and utilization of a class of 2,1-borazaronaphthyltrifluoroborate reagents that provide a general solution to the challenge of N-functionalization of the 2,1-borazaronaphthalene core is described. By adorning the nitrogen of this core with a trifluoroboratomethyl unit, a suite of odd-electron processes can be executed, installing motifs that would otherwise be inaccessible using a two-electron approach. In addition, this process enables rapid annulation, furnishing a heretofore unknown polycyclic B-N species.

Radical/Polar Annulation Reactions (RPARs) Enable the Modular Construction of Cyclopropanes.

An annulation process for the construction of 1,1-disubstituted cyclopropanes via a radical/polar crossover process is described. The cyclopropanation proceeds by the addition of a photocatalytically generated radical to a homoallylic tosylate. Reduction of the intermediate radical alkylation adduct (via single electron transfer) furnishes an anion that undergoes an intramolecular substitution. The process displays excellent functional group tolerance, characteristic of proceeding through odd-electron intermediates, and occurs under mild conditions with visible light irradiation.

Correction: Rapid access to diverse, trifluoromethyl-substituted alkenes using complementary strategies.

[This corrects the article DOI: 10.1039/C7SC05420C.].

3-Boryl-2,1-borazaronaphthalene: Umpolung Reagents for Diversifying Naphthalene Isosteres.

A Pd-catalyzed Miyaura borylation of 3-bromo-2,1-borazaronaphthalenes is reported. This method allows the formation of umpolung reagents for subsequent Pd-mediated cross-coupling. Coupling of this nucleophilic partner with a variety of commercially available aryl- and heteroaryl halides allows facile and rapid diversification of these cores.

Redox-Neutral Photocatalytic Cyclopropanation via Radical/Polar Crossover.

A benchtop stable, bifunctional reagent for the redox-neutral cyclopropanation of olefins has been developed. Triethylammonium bis(catecholato)iodomethylsilicate can be readily prepared on multigram scale. Using this reagent in combination with an organic photocatalyst and visible light, cyclopropanation of an array of olefins, including trifluoromethyl- and pinacolatoboryl-substituted alkenes, can be accomplished in a matter of hours. The reaction is highly tolerant of traditionally reactive functional groups (carboxylic acids, basic heterocycles, alkyl halides, etc.) and permits the chemoselective cyclopropanation of polyolefinated compounds. Mechanistic interrogation revealed that the reaction proceeds via a rapid anionic 3- exo- tet ring closure, a pathway consistent with experimental and computational data.

Engaging sulfinate salts via Ni/photoredox dual catalysis enables facile Csp2 -SO2R coupling.

This report details the development and implementation of a strategy to construct aryl- and heteroaryl sulfones via Ni/photoredox dual catalysis. Using aryl sulfinate salts, the C-S bond can be forged at room temperature under base-free conditions. An array of aryl- and heteroaryl halides are compatible with this approach. The broad tolerance and mild nature of the described reaction could potentially be employed to prepare sulfones with biological relevance (e.g., in bioconjugation, drug substance synthesis, etc.) as demonstrated in the synthesis of drug-like compounds or their precursors. When paired with existing Ni/photoredox chemistry for Csp3 -Csp2 cross-coupling, an array of diverse sulfone scaffolds can be readily assembled from bifunctional electrophiles. A mechanistic manifold consistent with experimental and computational data is presented.

Rapid access to diverse, trifluoromethyl-substituted alkenes using complementary strategies.

Two synergistic approaches to the facile assembly of complex α-trifluoromethyl alkenes are described. Using α-trifluoromethyl-ß-silyl alcohols as masked trifluoromethyl alkenes, cross-coupling or related functionalization processes at distal electrophilic sites can be executed without inducing Peterson elimination. Subsequent Lewis acidic activation affords functionalized α-trifluoromethyl alkenes. Likewise, the development of a novel α-trifluoromethylvinyl trifluoroborate reagent complements this approach and allows a one-step cross-coupling of (hetero)aryl halides to access a broad array of complex α-trifluoromethyl alkenes.

Oxidative functionalisation of alcohols and aldehydes via the merger of oxoammonium cations and photoredox catalysis.

We present a new paradigm for nitroxyl-mediated processes via the merger of oxoammonium cation-mediated oxidation with visible-light photoredox catalysis. The integration of these two forms of catalysis has been realised for the oxidative amidation of aldehydes, furnishing N-acylated heterocycles. Extension of this process to the oxidative amidation of alcohols via the intermediacy of an aldehyde was successfully pursued, thus proffering a general oxidation platform. The activated amides synthesised here are excellent synthetic handles for acylation.

Photoredox Generation of Carbon-Centered Radicals Enables the Construction of 1,1-Difluoroalkene Carbonyl Mimics.

Described is a facile, scalable route to access functional-group-rich gem-difluoroalkenes. Using visible-light-activated catalysts in conjunction with an arsenal of carbon-radical precursors, an array of trifluoromethyl-substituted alkenes undergoes radical defluorinative alkylation. Nonstabilized primary, secondary, and tertiary radicals can be used to install functional groups in a convergent manner, which would otherwise be challenging by two-electron pathways. The process readily extends to other perfluoroalkyl-substituted alkenes. In addition, we report the development of an organotrifluoroborate reagent to expedite the synthesis of the requisite trifluoromethyl-substituted alkene starting materials.

Haloselective Cross-Coupling via Ni/Photoredox Dual Catalysis.

The chemoselective functionalization of polyfunctional aryl linchpins is crucial for rapid diversification. Although well-explored for Csp2 and Csp nucleophiles, the chemoselective introduction of Csp3 groups remains notoriously difficult and is virtually undocumented using Ni catalysts. To fill this methodological gap, a "haloselective" cross-coupling process of arenes bearing two halogens, I and Br, using ammonium alkylbis(catecholato)silicates, has been developed. Utilizing Ni/photoredox dual catalysis, Csp3 -Csp2 bonds can be forged selectively at the iodine-bearing carbon of bromo(iodo)arenes. The described high-yielding, base-free strategy accommodates various protic functional groups. Selective electrophile activation enables installation of a second Csp3 center and can be done without the need for purification of the intermediate monoalkylated product.

Azaborininones: Synthesis and Structural Analysis of a Carbonyl-Containing Class of Azaborines.

An approach to access azaborininones (carbonyl-containing, boron-based heterocyclic scaffolds) using simple reagents and conditions from both organotrifluoroborates and boronic acids is described. An inexpensive, common reagent, SiO2, was found to serve as both a fluorophile and desiccant to facilitate the annulation process across three different azaborininone platforms. Computational analysis of some of the cores synthesized in this study was undertaken to compare the azaborininones with the analogous carbon-based heterocyclic systems. Computationally derived pKa values, NICS aromaticity calculations, and electrostatic potential surfaces revealed a unique isoelectronic/isostructural relationship between these azaborines and their carbon isosteres that changed based on boron connectivity. Correlation to experimentally derived data supports the computational findings.