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The present account summarises routes to tetralones, tetralines, and naphthalenes based on the chemistry of xanthates developed in the authors' laboratory. The degenerative reversible transfer of xanthates allows radical addition even to unactivated, electronically unbiased alkenes, and tolerates a broad range of functional groups, in particular common polar groups such as esters, ketones, nitriles, amides, carbamates

A convergent route to 1,3-dithiolan-2-ones based on the radical addition of xanthates to allylic acetates is described. The process is modular, uses inexpensive starting materials and reagents, and is atom economical, since both sulfur atoms of the xanthate end up in the products. With adducts derived from xanthates bearing an ester group, an unexpected transformation leading to lactones was uncovered.

5,5-Dithiospiroketals are prepared by a double radical addition of α,α'-bisxanthyl acetone to an alkene followed by ionic or thermal cleavage of the xanthate groups and acid-catalyzed ring closure. A modification employs α-chloro-α'-xanthyl acetone to give unsymmetrical derivatives. Reductive removal of the sulfur atoms with Raney nickel furnishes long-chain α,ω-diacids, diols, and diamines. Using biosourced alkenes, monomers and polymers can be obtained where essentially all the carbons are derived from the biomass.

A versatile strategy to access vicinally functionalized cyclopentanones and cyclohexanones is described. It takes advantage of new reagents, α-xanthyl enones, which can be prepared from the reaction of xanthate salts with the corresponding epoxyketones under mild conditions. β-Functionalization of these compounds can be performed by conjugate additions without affecting the xanthate moiety. This significantly expands the pool of xanthate substrates, allowing the synthesis of open chain and fused bicyclic building blocks useful in the synthesis of natural products.

Convergent routes to 1,3-dithian-2-ones based on the radical addition of xanthates to alkenes possessing a suitably located (latent) leaving group are described. These can be converted into 1,2-dithiolanes by base-mediated hydrolysis and oxidation. A broad variety of functional groups can be introduced, and the process is modular, uses inexpensive starting materials and reagents, and is atom economical, because both sulfur atoms of the xanthate end up in the products.

A versatile strategy to synthesize α,β-functionalized cyclopentanones and cyclohexanones is described. It takes advantage of new reagents, α-xanthyl enones, which can be prepared from the reaction of xanthate salts with epoxides under acidic conditions. β-Functionalization of these compounds can be performed by conjugate additions without affecting the xanthate moitety. This significantly expands the pool of xanthate substrates, allowing the synthesis of open chain and fused bicyclic building blocks useful in the synthesis of natural products.

International audience; This Perspective outlines the observations leading to the discovery of the degenerative exchange of xanthates and related thiocarbonylthio derivatives. It compares this process with the older Kharasch reaction and discusses the key ability to reversibly store active radicals in a nonreactive form. Implications for the synthesis of polymers beyond the RAFT/MADIX technology are discussed, namely, the modification of industrial polymers, the synthesis of novel monomers, oligomers, and surfactants from biosourced feedstocks, especially through an alliance with the powerful metathesis reaction. The synthesis of trialkoxysilane cross-linkers for sol–gels and the use of boronates for the construction of well-defined sequences by controlled insertion of single monomers are discussed briefly

International audience; Various protected β2-amino acids can be prepared by radical addition of β-phthalimido-α-xanthyl propionic acid, both as the free acid or as the ethyl ester. Successive radical additions provide access to more complex structures. In the case of the free acid, addition to certain heteroaromatics leads directly to β-heteroarylethylamines through spontaneous decarboxylation of the intermediate adduct. Forcing the decarboxylation in some cases generated a vinyl group by decarboxylative elimination of the phthalimido group.

A versatile strategy for the α-substitution of enones through the formal fusion between enones and unactivated alkenes is described. It relies on the formation and use of α-xanthyl-β-hydroxy ketones, which can be considered as synthetic equivalents of the high energy and difficult to tame alkenyl radicals. This approach thus constitutes a solution to the long-standing problem of sp2-sp3 bond formation in the α-position of enones and complements metal based methods that are more suitable for sp2-sp2 and sp2 -sp couplings. The functional group tolerance is particularly broad and the process, which can often be accomplished one-pot, could be extended in one case to an α,β-unsaturated ester.

This account relates briefly the personal trajectory of the author and the thought processes that went into solving synthetic problems and developing new reactions more generally useful in organic synthesis.1 Preamble and Early Education2 In France with Sir Derek Barton3 Chemistry at Ecole Polytechnique and at the ICSN4 Final Remarks

International audience; A modular approach to substituted cyclobutylboronic esters is described. It proceeds by successive intermolecular radical additions of xanthates to pinacolato 1-cyclobutenylboronate and to pinacolato bicyclo[1.1.0]but-1-ylboronate. Success hinges on tuning the stability of the a-boryl radical by exploiting the stabilizing influence of the trivalent boronic ester and the slightly destabilizing cyclobutane, which increases the s-character of the radical. Reductive removal of the xanthate group finally provides a range of 1,2-and 1,3disubstituted cyclobutylboronic esters. The contrast with cyclopropylboronic esters is striking, since the strong destabilization by the highly strained cyclopropane ring allows the first radical addition to take place but not the second. Furthermore, the first adducts are geminal xanthyl boronic esters that can be converted into cyclobutanones. This chemistry furnishes cyclobutylboronic esters that would be quite difficult to obtain otherwise and thus complements existing methods.

Pinacolato boronates (Bpin) with an empty p-orbital on boron stabilize an adjacent carbon radical, in contrast to diethanolamino boronates [B(DEA)] where the boron is sp3 -hybridized. By alternately placing a pinacol or diethanolamine moiety on the boron atom, thus stabilizing or not stabilizing the corresponding adjacent radical, it is possible to control the behavior of α-boronyl xanthates and construct a large variety of terminal or internal boronates in a modular fashion. The remarkable tolerance of polar groups and the ability to introduce quaternary centers are particularly noteworthy features of this process.

A series of conjugated 4-alkenyl-1,3-dithiol-2-ones have been prepared by microwave-assisted rearrangement of S-(4-acyloxy-2-alkynyl)- O-ethyl xanthates in moderate to good yields. The synthetic approach is based on a combination of [3,3] and [1,5] sigmatropic rearrangements as well as the intermediacy of a reactive betaine that induces the ionic elimination of the acyloxy group. The [1,5] sigmatropic rearrangement was confirmed by a deuterium-labeling experiment.

International audience; S-(1-Acetoxycyclobut-1-yl)-O-ethyl dithiocarbonate (xanthate) 7 was found to add to electronically unbiased alkene and to certain heteroarenes. In the latter case, this corresponds to a variant of the Minisci reaction and allows the late-stage modification of biologically active substances. Saponification of the acetate furnishes the corresponding cyclobutanol, which can be converted into fluorocyclobutanes by the action of DAST. Fluorocyclobutyl substituted aromatics and heteroaromatics are increasingly present in drug candidates. Finally, S-[1-(2',2',2'-trifluoroethoxy)cyclobut-1-yl]-O-ethyl dithiocarbonate 30 was obtained unexpectedly while optimizing the synthesis of xanthate 7 and found to be a very promising reagent for the introduction of the trifluoroethoxycyclobutyl motif.

International audience; Pyridoazepinones are a potentially interesting structures, yet still underexploited in the medicinal chemistry field and hard to obtain synthetically. We present a general and flexible synthetic route to substituted pyridoazepinones, enabled by the xanthate additiontransfer process, and furnishing the target molecules from readily available starting materials in generally good yields. The method shows good functional group tolerance and allows the preparation of pyridoazepinone scaffolds on gram scale.

Convergent routes to various six-membered carbocyclic architectures exploiting the unique radical chemistry of xanthates are described in this brief review. Three approaches are discussed. The first is the modification of existing cyclohexane building blocks, namely, cyclohexanones, cyclohexenones and cyclohexenes. The second deals with the construction of six-membered carbocycles by associating the chemistry of xanthates with classical ionic reactions, especially the Robinson annulation, the Michael addition and the Horner–Wadsworth–Emmons condensation. Finally, the third route is the formation of six-membered rings by direct six- exo and, but more rarely, six- endo cyclisation modes. Many of the complex structures presented herein would be tedious to obtain by more traditional methods.

International audience; The Barton-McCombie deoxygenation is a landmark reaction in organic chemistry. Its efficiency in generating carbon radicals from alcohols is unmatched, despite the passage of more than 40 years since its discovery. Its mechanism, far from being straightforward, is in fact quite subtle and conceptually part of a much larger family of very powerful thiocarbonyl controlled radical reactions. This general mechanistic manifold encompasses the degenerate transfer of xanthates and related thiocarbonylthio congeners, a process that also subtends the now popular RAFT/MADIX polymerization technology, the remarkably versatile Barton decarboxylation via thiohydroxamate esters, the generation of nitrogen-centered radicals from oxime xanthates and thiosemicarbazones and thiosemicarbazides, and certainly other transformations that will emerge in the coming years. The present overview retraces the history of the Barton-McCombie reaction, the evolution of the mechanistic aspects and the resulting consequences in terms of new transformations and synthetic applications.

ConspectusThe alkylation of enolates is one of the backbones of ketone chemistry, yet in practice it suffers from numerous limitations due to problems of regiochemistry (including O- versus C-alkylation), multiple alkylations, self-condensation, competing elimination, and incompatibility with many polar groups that have to be protected. Over the years, various solutions have been devised to overcome these difficulties, such as the employment of auxiliary ester or sulfone groups to modify the pKa of the enolizable hydrogens, the passage by the corresponding hydrazones, the use of transition-metal-catalyzed redox systems to formally alkylate ketones with alcohols, etc. Most of these hurdles disappear upon switching to α-ketonyl radicals. Radicals are tolerant of most polar functions, and radical additions to flat sp2 centers are generally easier to accomplish than enolate substitution at tetrahedral sp3 carbons. The main stumbling block, however, has been a lack of generally applicable methods for the gener...

International audience; The xanthate-mediated addition of tertiary alkyl radicals to heteroarenes enabled the easy functionalization of heteroaromatic rings as well as more decorated structures, such as marketed drugs or agrochemicals. This work provides a synthetic tool for efficiently exploring the chemical space by allowing late-stage diversification with a high tolerance toward functional groups.

International audience; The first examples of direct synthesis of γ-thiolactones by addition of a thiolactone-based radical are described. Mono- and bis-γ-thiolactones can be obtained by a dilauroyl peroxide initiated addition of thiolactone xanthate to various alkenes and α,ω-dienes. The process is modular and exhibits a high functional group tolerance.

International audience; A direct and efficient introduction of a trifluoroethylamine motif into various heteroaromatic structures, using a readily available xanthate S-[1-(N-acetylamino)-2,2,2-trifluoroethyl]-O-ethyl dithiocarbonate (5), is reported. Medicinally relevant trifluoroethylaminated heteroarenes containing a wide range of functional groups were successfully synthesized under mild conditions. This amide isostere could be introduced into both electron-rich and -poor heteroarenes to give the desired products in one step. The beneficial effect of camphorsulfonic acid (CSA) was also demonstrated with electron-deficient heteroarenes.

International audience; A novel radical cascade reaction of xanthates with 1-[(vinyldimethylsilyl)oxy]cyclohex-2-enes is developed. Due to the steric and electronic differentiation of the two olefinic functions, exclusive regioselectivity and high stereoselectivity of the addition-cyclization are observed. Several methods for modification of both the silicon tether and the xanthate function are reported.

Convergent routes to a variety of pyridines involving radical additions of xanthates are described. Emphasis is placed on reactions leading to tetrahydropyridines, which can be oxidized to pyridines, and to the formation of 1,5-diketones or 1,5-ketoaldehydes or their synthetic equivalents, which can then be condensed with ammonium acetate/–acetic acid under air in a variation of the classical synthesis of pyridines. The construction of pyridines fused to five-, six-, and seven-membered rings by intramolecular radical additions to the pyridine nucleus is also presented in detail. These include azaoxindoles, azaindolines, azaindoles, azaindanes, tetrahydronaphthyridines, and tetrahydropyridoazepines. Finally, the modification of pyridines by direct radical addition is discussed.

International audience; Convergent routes to a variety of indolines, indoles, oxindoles, and their aza analogues involving radical additions of xanthates are described. Three approaches are summarized. The first is the least general and relies on the generation of aryl or heteroaryl radicals starting from diazonium salts. The second involves radical addition to N-allylanilines followed by ring-closure onto the aromatic core. A large variety of indolines and azaindolines can thus be obtained and, in many cases, converted into the corresponding indoles and azaindoles by various methods. The synthesis of novel fluoroazaindolines and fluoroazaindoles by a rare homolytic ipso-substitution of fluorine atoms is particularly noteworthy. The last approach hinges on the direct modification of indoles by radical addition to the pyrrole subunit of the indole nucleus. Application of this methodology to the total synthesis of melatonin and the alkaloids mersicarpine, caulerpine, and the pentacyclic skeleton of tronocarpine is briefly discussed. Most of the compounds described herein would be difficult to obtain by more traditional routes.

This review discusses the numerous routes to all-carbon quaternary centers based on the unique radical chemistry of xanthates. It summarizes the various approaches to the synthesis of tertiary xanthates then describes the intra- and intermolecular radical additions and combinations thereof that have so far been used to construct quaternary centers.

O-Neopentyl-xanthate 19 bearing a masked α-amino aldehyde, with the two functional groups orthogonally protected, reacts cleanly with many functional alkenes. The radical addition–transfer furnishes densely functionalized adducts that can be further transformed into an array of amino-substituted carbocycles and heteroaromatics. They are also easily converted into imidazolones.

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International audience; The radical addition of xanthates to N,N-diacetyl imidazol-2-one can be followed by a second addition to N,N-di-Boc imidazol-2-one to give after reductive dexanthylation a protected tetra-amine possessing four contiguous carbon–nitrogen bonds, or even five if the starting xanthate itself bears a protected amine. The success of this sequence hinges on the difference in radical stability between radicals substituted by an N-acyl and N-carbamoyl nitrogens, which allows control of the radical addition and prevents the formation of oligomers.

The present brief account relates synthetic endeavours revolving around a novel chemistry of xanthates (dithiocarbonates) being developed in our group. The degenerative reversible transfer of xanthates has a unique ability to store reactive radicals in a dormant form, and thereby to enhance their lifetime in a concentrated medium, while at the same time, regulating their absolute and relative concentrations. It allows intermolecular radical additions even to unactivated alkenes, and can promote otherwise sluggish radical processes, such as 5-endo, 6-exo, 6-endo, 7-endo, and 8-endo cyclisations, as well as ring closures on (hetero)aromatic structures. This chemistry has proved remarkably versatile and powerful, both for solving synthetic problems and for the industrial production of block copolymers through the RAFT/MADIX technology.

International audience; The S-propargyl xanthate derived from ethyl (S)-lactate reacts upon heating with various acidic substances to give the propionate transfer product in high yield and with complete inversion of configuration.

International audience; Convergent routes to various classes of lactams exploiting the unique radical chemistry of xanthates are described. Emphasis is placed on reactions leading to lactams by direct radical cyclization, by intermolecular additions to alkenes followed by ring closure, and by radical additions to alkenes furnishing amino esters and aminoacids precursors that can be converted into lactams by ionic condensations. The possibility of modifying existing lactam structures is briefly discussed. Four-, five-, six-, seven-and, more rarely, eight-membered lactams can be constructed, including five-, six-, seven-membered lactams fused to aromatic and heteroaromatic rings. The latter are exemplified by oxindoles, azaoxindoles, tetrahydroquinolones, tetrahydroisoquinolones tetrahydroazaquinolones, tetrahydrobenazepinones, and tetrahydropyridoazepinones.

S-Propargyl xanthates undergo upon heating a [3,3] sigmatropic rearrangement followed by a reversible ring closure into a novel betaine. This betaine can be implicated in carbon–carbon bond forming processes, in the synthesis of esters, in the inversion of secondary alcohols, in the formation of alkenes, for the generation of rigid, cisoid dienes that are highly reactive in both inter- and intra-molecular Diels–Alder cycloadditions, and in various other synthetically useful transformations.1 Introduction2 An Unexpected Transformation3 Evidence for the Betaine Intermediate4 A Method for the Synthesis of Esters and for the Inversion of Secondary Alcohols5 A General Alkylation Process6 The Case of Carbon Acids7 A Synthesis of Alkenes8 Further Trapping Experiments. Concerted or Not Concerted?9 Rigid Cisoid Dienes10 Propargyl Radicals11 Concluding Remarks

International audience; An expedient approach for the intermolecular C-H functionalization of pyrazines and other heteroarenes by the radical chemistry of xanthates is reported. Incorporation of a multitude of functional alkyl groups onto these heteroarenes proceeds in good yield and good to excellent regioselectivity, leading to highly functionalized heteroaromatics.

International audience; The radical addition of dithiocarbonates to 1,1-bis(boronyl)-3-butene and related alkenes occurs without complications from fragmentation or hydrogen atom abstraction and delivers a vast array of highly functional geminal bis(boronates). The ability to assemble geminal bis(boronates) bearing polar functional groups not readily obtained through existing methods is particularly noteworthy. This approach also opens up access to geminal bis(boronyl) cyclopropanes and geminal bis(boronyl) tetrahydroquinolines.

International audience; A simple method for the introduction of a methyl and higher aliphatic group to various heteroarenes using very inexpensive reagents is described. It is based on the radical addition of a carboxylic xanthate followed by decarboxylation. Depending on the heteroarene structure, the decarboxylation can be spontaneous or induced by heating in N,N-dimethylacetamide or N-methyl pyrrolidone in a microwave oven.

An overview of a convergent, modular route to protected amines, anilines, and related compounds hinging on the degenerate radical addition-transfer of xanthates is presented. Emphasis is placed on the importance of the stabilization of the starting radical by imides and other structures. 1 Introduction 2 The Degenerate Xanthate Transfer Process and Examples of Amine Synthesis 3 Stabilization of Radicals by Imides. Initial Observations and the Radical Aminomethylation of Alkenes 4 More Elaborate Phthalimide-Substituted Xanthates 5 Polyamines and β-Lactams 6 Anilines and Related Derivatives 7 Further Synthetic Variations 8 Outlook and Perspectives

International audience; The synthesis of a new fluorinated reagent O-ethyl S-(1,2,2,2-tetrafluoroethyl) carbonodithioate (xanthate) and its use for the generation and capture of the hitherto unexplored 1,2,2,2-tetrafluo­roethyl radicals is described. This reagent allows the convenient introduction of the rare CF3CHF motif onto various olefinic substrates with a high functional-group tolerance.

A simple radical-based route to gem-α-dichloroketones, relying on the degenerative addition transfer of (S)-[3,3-dichloro-2-oxopropyl]-O-ethyl dithiocarbonate (xanthate), is described. The adducts can then be converted into Z-enoates by exposure to Et3N in methanol. In the case of certain substrates, it was possible to form skipped dienoic acid and methyl E,E-dienoates.

International audience; An efficient protocol for the preparation of S-(1-chloro-2,2,2-trifluoroethyl)-O-ethyl xanthate is reported. This reagent serves as a versatile precursor of highly functionalized gem-difluoroalkenes through various inter- and intramolecular radical reactions and subsequent reduction with activated magnesium metal. (C) 2014 Elsevier Ltd. All rights reserved.