Some Aspects of α-(Acyloxy)alkyl Radicals in Organic Synthesis.

The preparation and use of α-(acyloxy)alkyl xanthates to generate and capture α-(acyloxy)alkyl radicals is briefly reviewed. Their inter- and intramolecular additions to both activated and unactivated, electronically unbiased, alkenes, and to (hetero)aromatic rings, as well as their radical allylation and vinylation reactions are described. Application to the total synthesis of two 4-hydroxytetralone natural products is also presented.

The xanthate route to tetralones, tetralins, and naphthalenes. A brief account.

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, etc. Xanthates also allow radical ring closures onto aromatic rings. This feature, in combination with the intermolecular addition to alkenes, can be used to construct tetralones and tetralines. With the appropriate appendages, the former can be converted into napthalenes with a variety of substitution patterns. This translates into a convergent approach to a vast array of building blocks of interest to the pharmaceutical and agrochemical industries, and to material sciences.

A Route to 5,5-Dithiospiroketals and to Long-Chain Monomers from the Biomass.

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.

Some aspects of radical cascade and relay reactions.

The ability to create carbon-carbon bonds is at the heart of organic synthesis. Radical processes are particularly apt at creating such bonds, especially in cascade or relay sequences where more than one bond is formed, allowing for a rapid assembly of complex structures. In the present brief overview, examples taken from the authors' laboratory will serve to illustrate the strategic impact of radical-based approaches on synthetic planning. Transformations involving nitrogen-centred radicals, electron transfer from metallic nickel and the reversible degenerative exchange of xanthates will be presented and discussed. The last method has proved to be a particularly powerful tool for the intermolecular creation of carbon-carbon bonds by radical additions even to unactivated alkenes. Various functional groups can be brought into the same molecule in a convergent manner and made to react together in order to further increase the structural complexity. One important benefit of this chemistry is the so-called RAFT/MADIX technology for the manufacture of block copolymers of almost any desired architecture.

Radical Instability in Aid of Efficiency: A Powerful Route to Highly Functional MIDA Boronates.

The inability of the sp(3) boron in MIDA boronates to stabilize an adjacent radical makes possible the efficient addition of a wide array of xanthates to vinyl MIDA boronate, leading to highly functionalized and diverse aliphatic organoboron structures. The lack of radical stabilization also allows the exchange of the xanthate in the adducts with a bromine. In one case, the bromine was substituted to generate a cyclopropyl MIDA derivative.

Allylic alcohols: ideal radical allylating agents?

Radical allylations represent effective routes to various alkenes, but to date they have relied chiefly on organostannane derivatives and still suffer from significant limitations with respect to the substitution pattern of the starting allylating agent. Indeed, while substituents at the ß-position relative to the radical leaving group are well-tolerated, introduction of α-substituents induces a major complication due to the rapid and usually irreversible isomerization of the starting allylating agents. Although a number of research groups have made substantial efforts to develop heavy-metal-free radical allylations, methods compatible with α-substitution of the allylating agent are still scarce. Furthermore, quite a few systems are limited by the relative inaccessibility of the substrates. This Account summarizes our sustained efforts regarding the development of allylic alcohols into "ideal" radical allylating agents and presents published as well as some unpublished results. The systems we have developed combine the use of readily available xanthates and allylic alcohol derivatives under metal-free conditions to furnish not only alkenes but also aldehydes and saturated and unsaturated ketones through the virtually unprecedented homolytic cleavage of the normally strong C-O or C-C bond. The former route hinges on first converting the allylic alcohol into a 2-fluoro-6-pyridoxy derivative by reacting the corresponding alcoholate with 2,6-difluoropyridine, while the latter relies on attaching a cumyl group to the carbon bearing the free allylic alcohol. Either substrate is then exposed to the action of a suitable xanthate in the presence of a stoichiometric amount of a peroxide, usually lauroyl peroxide (DLP) in refluxing ethyl acetate or di-tert-butyl peroxide (TBHP) in refluxing chlorobenzene for the more difficult cases. Even though C-O or C-C bond homolysis leads to a stabilized 2-fluoro-6-pyridinyloxyl radical or a cumyl radical, respectively, the ß-scission in both cases is relatively slow and at the lower limit of useful elementary radical steps. The kinetic barrier of the fragmentation can nevertheless be overcome because of the long relative lifetime of radicals generated by the degenerate transfer of the xanthate group, and this is a key element for success. This novel technology offers numerous advantages. The starting activated allylic alcohol derivatives are readily accessible in two steps from aldehydes or ketones. They can also be obtained by base-induced opening of epoxides. Numerous functional groups are tolerated under the mild reaction conditions for the radical addition-elimination, as nicely illustrated by over 150 examples of radical allylations, not all of which can be included in the present Account. In addition, substitution at both the α- and ß-positions of the allylating agent is possible, a rare feature in this area.

A radical thia-Brook rearrangement.

Geminal mercapto trialkyl- and trialkoxy-silanes undergo an efficient radical chain rearrangement, whereby the silyl group migrates from carbon to sulfur; the starting materials are readily obtained by exploiting the peroxide initiated radical addition of dithiocarbonates (xanthates) to trialkyl- or trialkoxy-vinylsilanes.

A direct, versatile route to functionalized trialkoxysilanes.

The peroxide initiated radical addition of dithiocarbonates (xanthates) to trialkoxy vinylsilanes leads to functionalized trialkoxysilanes. Prior addition of the dithiocarbonates to an alkene before reaction with the vinylsilane can be used to increase the complexity of the final product.

Flexible routes to thiophenes.

Three convergent routes to thiophenes are described, hinging on the radical addition of α-xanthyl ketones to ethyl vinyl sulfide or to vinyl pivalate. The latter route ultimately proved to be the most versatile and efficient (61-94%).

An expedient route to dihydrothiazines, a virtually unknown class of heterocycles.

Upon heating at 180-200 °C in diphenyl ether, S-(4-oximinoalkyl)xanthates with a secondary isopropyl or isobutyl group on the oxygen undergo a Chugaev elimination followed by ring closure onto the oxime to give dihydrothiazines, a virtually unknown class of heterocycles.

Tri- and tetrasubstituted functionalized vinyl sulfides by radical allylation.

2-Fluoropyridinyl-6-oxy- precursors derived from phenyl vinyl sulfide react with radicals generated from xanthates via an addition-elimination process to furnish the corresponding vinyl sulfides in good yields. This convergent method is operationally simple and enables a straightforward synthesis of the difficult to access tetrasubstituted vinyl sulfides. Vinyl sulfides were used as more robust enol ether surrogates in highly stereoselective reactions with N-acylium cations leading to nitrogen-containing polycyclic structures.

Some aspects of radical chemistry in the assembly of complex molecular architectures.

This review article describes briefly some of the radical processes developed in the authors' laboratory as they pertain to the concise assembly of complex molecular scaffolds. The emphasis is placed on the use of nitrogen-centred radicals, on the degenerate addition-transfer of xanthates, especially on its potential for intermolecular carbon-carbon bond formation, and on the generation and capture of radicals through electron transfer processes.

An unusual synthesis of N-unsubstituted benzazepinones.

A short route to novel bicyclic N-unprotected benzazepinones is described starting from N-acetoxyanilides involving radical addition and cyclization with concomitant homolytic rupture of the N-O bond.

A convergent, unified approach to functionalized fluoro- and trifluoromethyl alkenes.

A modular, convergent, and operationally simple route to trifluoromethyl alkenes and vinyl fluorides involving a unique carbon-oxygen bond homolysis is reported. Highly functionalized trifluoromethyl alkenes and vinyl fluorides were obtained in good yields and good selectivity.

Some aspects of the radical chemistry of xanthates.

Xanthates and related thiocarbonylthio derivatives have proved to be exceedingly useful substrates for both inter- and intra- molecular radical additions. The intermolecular addition to unactivated alkenes, in particular, provides tremendous opportunities for synthesis: various functional groups can be brought together under mild, neutral conditions. Since the adduct is also a xanthate, iteration allows the formation of block polymers through a controlled radical polymerisation (the RAFT/MADIX technology). Also of some importance is the access to highly substituted aromatic and heteroaromatic derivatives.

A unified access to diverse heteroaromatic scaffolds using the radical chemistry of xanthates.

The degenerate transfer of xanthates allows generally difficult radical transformations, such as intermolecular additions to unactivated alkenes and cyclisations onto aromatic and heteroaromatic rings, to be accomplished under very practical experimental conditions. This translates into numerous approaches for the construction or modification of heteroaromatic structures. The present report aims to provide a brief overview of the various synthetic possibilities, with particular emphasis on medicinally interesting families of compounds.

Elimination versus ring opening: a convergent route to alkylidene-cyclobutanes.

Functionalized alkylidene-cyclobutanes have been prepared from 2-fluoropyridinyl-6-oxy precursors derived from vinyl cyclobutanols by a radical addition-elimination process. A wide range of functional groups is tolerated, and the alkylidene-cyclobutanes can be further elaborated into cyclopentanones. The limitation of this approach resides in the competition with opening of the cyclobutane ring.

Modular approach to saturated and α,ß-unsaturated ketones.

2-Fluoro-6-pyridinyloxy derivatives of 2-ethoxyvinyl carbinols react with radicals derived from xanthates by an addition-fragmentation pathway to give highly functionalized ketones after acid hydrolysis. 1,4-Diketones are readily accessible by this approach. α,ß-Unsaturated ketones can be obtained by starting with geminal acetoxy xanthates prepared by addition of a simpler xanthate to vinyl acetate.

A highly stereoselective, modular route to (E)-vinylsulfones and to (Z)- and (E)-alkenes.

A recently discovered radical fragmentation of 2-fluoro-6-pyridinoxy derivatives allows a new highly stereoselective and convergent route to (E)-vinylsulfones from allylic alcohols. Reductive desulfonylation or nickel-catalyzed couplings furnish di- and trisubstituted (E)- and (Z)-alkenes.

Oxime derivatives as α-electrophiles. from α-tetralone oximes to tetracyclic frameworks.

When subjected to the conditions of a Semmler-Wolff/Schroeter aromatization, the oximes of 4-benzyl-substituted tetralones undergo an electrophilic aromatic substitution reaction to form tetracyclic frameworks.