The catalytic conversion of chemical feedstocks into products of medicinal and agricultural value is a key theme across modern synthetic chemistry. As 1,3-dienes are readily available from industrial ...cracking processes, there is great interest in the development of sustainable methods for the functionalization of these simple molecules. Although initial developments in this field have required precious-transition-metal catalysts, there has been a push toward the use of inexpensive, nontoxic, and more abundant copper catalysts to promote functionalization. This Perspective covers the many developments in the area of copper-catalyzed functionalization of 1,3-dienes, in particular hydrofunctionalization, borofunctionalization, and difunctionalization (e.g., diamination).
Sulfoxides are classical functional groups for directing the stoichiometric metalation and functionalization of C−H bonds. In recent times, sulfoxides have been given a new lease on life owing to the ...development of modern synthetic methods that have arisen because of their unique reactivity. They have recently been used in catalytic C−H activation proceeding via coordination of an internal sulfoxide to a metal or through the action of an external sulfoxide ligand. Furthermore, sulfoxides are able to capture nucleophiles and electrophiles to give sulfonium salts, which subsequently enable the formation of C−C bonds at the expense of C−H bonds. This Review summarizes a renaissance period in the application of sulfoxides arising from their versatility in directing C−H functionalization.
Classical sulfoxide directing groups have been given a new lease on life because of their unique ability to direct a variety of C−H couplings to form important C−C bonds. Sulfoxide direction operates through internal coordination to a metal (directing groups), through external coordination (ligands), or via sulfoxide capture of nucleophilic or electrophilic coupling partners (sulfonium‐directed).
The photoactivation of electron donor-acceptor complexes has emerged as a sustainable, selective and versatile strategy for the generation of radical species. However, when it comes to aryl radical ...formation, this strategy remains hamstrung by the electronic properties of the aromatic radical precursors, and electron-deficient aryl halide acceptors are required. This has prevented the implementation of a general synthetic platform for aryl radical formation. Our study introduces triarylsulfonium salts as acceptors in photoactive electron donor-acceptor complexes, used in combination with catalytic amounts of newly designed amine donors. The sulfonium salt label renders inconsequential the electronic features of the aryl radical precursor and, more importantly, it is installed regioselectively in native aromatic compounds by C-H sulfenylation. Using this general, site-selective aromatic C-H functionalization approach, we developed metal-free protocols for the alkylation and cyanation of arenes, and showcased their application in both the synthesis and the late-stage modification of pharmaceuticals and agrochemicals.
Ketyl radicals are valuable reactive intermediates for synthesis and are used extensively to construct complex, functionalized products from carbonyl substrates. Single electron transfer (SET) ...reduction of the C&z.dbd;O bond of aldehydes and ketones is the classical approach for the formation of ketyl radicals and metal reductants are the archetypal reagents employed. The past decade has, however, witnessed significant advances in the generation and harnessing of ketyl radicals. This tutorial review highlights recent, exciting developments in the chemistry of ketyl radicals by comparing the varied contemporary - for example, using photoredox catalysts - and more classical approaches for the generation and use of ketyl radicals. The review will focus on different strategies for ketyl radical generation, their creative use in new synthetic protocols, strategies for the control of enantioselectivity, and detailed mechanisms where appropriate.
Ketyl radicals are valuable reactive intermediates for synthesis. This review highlights exciting recent developments in the chemistry of ketyl radicals by comparing contemporary and more classical approaches for their generation and use.
Reductive electron transfer (ET) to organic compounds is a powerful method for the activation of substrates via the formation of radicals, radical anions, anions, and dianions that can be exploited ...in bond-cleaving and bond-forming processes. Since its introduction to the synthetic community in 1977 by Kagan, SmI2 has become one of the most important reducing agents available in the laboratory. Despite its widespread application in aldehyde and ketone reduction, it was widely accepted that carboxylic acid derivatives could not be reduced by SmI2; only recently has our work led to this dogma being overturned, and the reduction of carboxylic acid derivatives using SmI2 can now take its place alongside aldehyde/ketone reduction as a powerful activation mode for synthesis. In this Account, we set out our studies of the reduction of carboxylic acid derivatives using SmI2, SmI2–H2O, and SmI2–H2O–NR3 and the exploitation of the unusual radical anions that are now accessible in unprecedented carbon–carbon bond-forming processes. The Account begins with our serendipitous discovery that SmI2 mixed with H2O is able to reduce six-membered lactones to diols, a transformation previously thought to be impossible. After the successful development of selective monoreductions of Meldrum’s acid and barbituric acid heterocyclic feedstocks, we then identified the SmI2–H2O–NR3 reagent system for the efficient reduction of a range of acyclic carboxylic acid derivatives that typically present a significant challenge for ET reductants. Mechanistic studies have led us to propose a common mechanism for the reduction of carboxylic acid derivatives using Sm(II), with only subtle changes observed as the carboxylic acid derivative and Sm(II) reagent system are varied. At the center of our postulated mechanism is the proposed reversibility of the first ET to the carbonyl of carboxylic acid derivatives, and this led us to devise several strategies that allow the radical anion intermediates to be exploited productively in efficient new processes. First, we have used internal directing groups in substrates to “switch on” productive ET to esters and amides and have exploited such an approach in tag-removal cyclization processes that deliver molecular scaffolds of significance in biology and materials science. Second, we have exploited external ligands to facilitate ET to carboxylic acid derivatives and have applied the strategy in telescoped reaction sequences. Finally, we have employed follow-up cyclizations with alkenes, alkynes, and allenes to intercept radical anion intermediates formed along the reaction path and have employed this strategy in complexity-generating cascade approaches to biologically significant molecular architectures. From our studies, it is now clear that Sm(II)-mediated ET to carboxylic acid derivatives constitutes a general strategy for inverting the polarity of the carbonyl, allowing nucleophilic carbon-centered radicals to be formed and exploited in novel chemical processes.
Recently, samarium(
ii
) iodide reductants have emerged as powerful single electron donors for the highly chemoselective reduction of common functional groups. Complete control of the product ...formation can be achieved on the basis of a judicious choice of a Sm(
ii
) complex/proton donor couple, even in the presence of extremely sensitive functionalities (iodides, aldehydes). In most cases, the reductions are governed by thermodynamic control of the first electron transfer, which opens up new prospects for unprecedented transformations
via
radical intermediates under mild regio-, chemo- and diastereoselective conditions that are fully orthogonal to hydrogenation or metal-hydride mediated processes.
Recently, samarium(
ii
) iodide reductants have emerged as powerful single electron donors for the highly chemoselective reduction of common functional groups.
Sulfonium salts are playing an increasingly significant role in contemporary organic synthesis. In particular, the generation of radicals from sulfonium salts is a fundamental process in Nature and ...has been the subject of investigation for over 50 years. However, general synthetic methods that use sulfonium salts as radical precursors are rare. The advent of photoredox catalysis has triggered an upsurge of interest in the radical chemistry of sulfonium salts and this review surveys recent applications of aryl‐ and alkylsulfonium salts in light‐mediated, radical C−C bond formation.
C(sp
)-rich bicyclic hydrocarbon scaffolds, as exemplified by bicyclo1.1.1pentanes, play an increasingly high-profile role as saturated bioisosteres of benzenoids in medicinal chemistry and crop ...science. Substituted bicyclo2.1.1hexanes (BCHs) are emerging bicyclic hydrocarbon bioisosteres for ortho- and meta-substituted benzenes, but are difficult to access. Therefore, a general synthetic route to BCHs is needed if their potential as bioisosteres is to be realized. Here we describe a broadly applicable catalytic approach that delivers substituted BCHs by intermolecular coupling between olefins and bicyclo1.1.0butyl (BCB) ketones. The SmI
-catalysed process works for a wide range of electron-deficient alkenes and substituted BCB ketones, operates with SmI
loadings as low as 5 mol% and is underpinned by a radical relay mechanism that is supported by density functional theory calculations. The product BCH ketones have been shown to be versatile synthetic intermediates through selective downstream manipulation and the expedient synthesis of a saturated hydrocarbon analogue of the broad-spectrum antimicrobial, phthalylsulfathiazole.
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