Radicals in Action: A Festival of Radical ... - ACS Publications

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Radicals in Action: A Festival of Radical Transformations almost simultaneously by the groups of Pasto and Whitesides.7 Thus, the reductive demercuration of compounds such as 1 proceeds via organomercuric hydride 3 possessing a particularly weak mercury−hydrogen bond. In the presence of oxygen or traces of transition metals, it spontaneously gives rise to a small amount of radical 4, which extrudes metallic mercury to liberate carbon radical 5. The latter rapidly abstracts a hydrogen atom from hydride 3 to give the observed reduced product 2. This explains the lack of stereoselectivty when deuteroborohydride is used, an observation that could not be rationalized by any satisfactory ionic mechanism. In 1975, Barton and McCombie described a remarkable deoxygenation method, applicable to structures of great complexity.8 This powerful reaction acted as an eye opener to tremendous synthetic potential of radical chemistry. The deoxygenation of aminoglycoside 6 via xanthate 7 reported by Hayashi and co-workers in 1978 (Scheme 2) is an early

T

his modified anonymous limerick1 encapsulates the suspicious attitude of many chemists toward radical reactions. Even now, radicals still occasionally conjure up visions of runaway reactions, of messy black tars, and of intractable mixtures. Indeed, for a long time the importance of radicals as synthetically useful reactive intermediates was little appreciated outside of the polymer field. Sir Christopher Ingold famously stated that “Homolysis, even between consenting adults, is grounds for instant dismissal from this Department”.2 Morris Kharasch, one of the fathers of modern radical chemistry (and a remarkably original thinker3), became so frustrated with his manuscripts being rejected by the reviewers of his day that he used his influence to convince the ACS Board to launch The Journal of Organic Chemistry. Being on the Board of Editors made it easier for him to identify reviewers with the correct expertise.4 Thus, whereas the impact of radical processes on the polymer industry was swift, dramatic, and continuous, their application to organic synthesis, both in academia and industry, was slow and bumpy. Most household plastics, such as (low density) polyethylene, polystyrene, PVC, polyacrylate fibers, Plexiglas (poly( methyl methacrylate)), Teflon (polytetrafluoroethylene), and ABS rubber (acrylonitrile-butadienestirene copolymer) are manufactured industrially by radical polymerization, many on multimillion metric ton scale.5 In contrast, the use of radical reactions for the synthesis of small molecules remained sporadic until the 1970s. The chlorination of alkanes and the allylic bromination with NBS (the Wohl− Ziegler reaction) were perhaps the only reactions described to undergraduates as radical processes, even if the exact mechanism of the latter was not very clear at the time.6 Other transformations were employed without realization of the radical nature of the intermediates. These include, for example, the classical reductive demercuration depicted in Scheme 1, the radical mechanism of which was unraveled

Scheme 2. A Spectacular Early Example of the Barton− McCombie Deoxygenation

application of the Barton−McCombie deoxygenation.9 Even now, nearly 40 years later, it would still be extremely tedious to accomplish this transformation by any other method. The landmark discovery of Barton and McCombie coincided with the availability of reliable rate constants (“radical horlogerie” 10) derived from laser flash photolysis and competition experiments.11 These kinetic data confirmed the high speed of formation of five-membered rings by 5-exo ring closures, noted initially by polymer chemists,12 and laid the foundations for spectacular cascades, such as the pioneering synthesis of hirsutene by Curran13 (probably still the shortest) or the development of the remarkable silicon-tether strategy of Stork and Ueno.14 The importance of the contribution of physical organic chemists to the renaissance of radical chemistry that erupted in the last quarter of the 20th century cannot be overstated. The rates of most elementary steps in ionic and organometallic chemistry are on a human time scale: minutes, hours, days. The rates for most elementary radical steps in contrast range from a tenth of a second to a nanosecond and even less, well beyond the perception of human beings.15 Without ultrafast kinetic measurements, these elementary steps cannot be ranked and, ultimately, controlled. Nor can the experiments be rationally designed to guide the radical sequence toward the formation of

Scheme 1. Reductive Demercuration Is a Radical Reaction

Received: February 21, 2017 Published: March 17, 2017 © 2017 American Chemical Society

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DOI: 10.1021/acs.orglett.7b00531 Org. Lett. 2017, 19, 1257−1269

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and easily gives hydroxide anions, but it is a strong bond and very resistant to homolysis, leading to the high-energy hydroxyl radical. Indeed, most industrial emulsion radical polymerizations are carried out in water. In addition to being a “green” solvent par excellence, water is the “solvent” in all living organisms. Nature has therefore by necessity made extensive use of radical reactions.16 It has learned to tame and handle triplet oxygen; it devised complex systems such as glutathione and glutathione peroxidase to offset the onslaughts of superoxide, hydroxyl, and other nefarious radical species;17 it developed a range of oxidizing reagents, such as the cytochromes, to modify and ultimately degrade a broad array of endogenous and exogenous substances;18 it elaborated the exquisite cobalt-based radical chemistry of vitamin B1219 and the superfamily of enzymes (several tens of thousands of members!) involving S-adenosyl methionine radicals,20 and so on and so forth. The supremely important biosynthesis of deoxyribonucleotides involves a radical-based deoxygenation of ribose units mediated by a highly conserved iron-dependent enzyme called ribonucleotide reductase.21 Improved understanding of radical processes will therefore lead to a better comprehension of numerous biological mechanisms. For instance, many of these processes revolve around persistent radicals, such as triplet oxygen and cobalt(II) species, and are therefore under the control of the “persistent radical effect”, also called the Fischer−Ingold effect.22 It explains how, by selectively capturing all other radicals, a persistent radical23 causes the exclusive formation of the crosscoupled derivatives, instead of the useless mixture of all possible radical−radical coupling products. It is indeed quite remarkable that ultrafast radical−radical interactions that proceed at nearly diffusion rates can be so efficiently controlled. My acquaintance with the Fischer−Ingold effect occurred in a rather amusing manner. In late 1983, I was appointed as one of three junior lieutenants in the group of the late Sir Derek Barton. I was put in charge of the team working on radical reactions, even though my previous training did not involve any significant radical chemistry (it may surprise many, but I have done very little radical chemistry with my own hands). I therefore had to spend quite a bit of time catching up on the basics and on the more recent literature. Sometime late in 1985, Professor Barton called me up to his office and handed me a typed manuscript to read. It was by Hanns Fischer, as the sole author, and had a somewhat cryptic title: “Unusual Selectivities of Radical Reactions by Internal Suppression of Fast Modes”.22 This article had not yet appeared in press and was presumably still being evaluated by the referees. Nevertheless, I tried to study its contents so as not to look a fool in case Professor Barton questioned me about it. This was very fortunate, because I may have otherwise missed this landmark paper or only looked at it very superficially when routinely flicking through the journals. The importance of the persistent radical effect became immediately apparent at the time, even to the novice I was; but how really important this principle actually is only percolated over many years. This relatively little-known concept has extraordinarily far-reaching consequences; indeed, it represents in my view one of the most significant conceptual advances in chemistry in the last 30 years.24 Nitroxide-mediated polymerization (NMP), a technology for the synthesis of block copolymers, depends totally on the properties of persistent nitroxyl radicals such as TEMPO.25 In addition to Co(II), mentioned above in relation to vitamin B12, Cu(II), Fe(III), Ti(III), and Ru(III) complexes are also

the desired product with a minimum of side reactions, resulting, for example, from radical−radical interactions or attacks on the solvent. The former often occur at diffusion controlled rates and can only be avoided by keeping the radical concentration extremely low. Thus, in striking contrast to ionic and organometallic chemistry, where knowledge of reaction rates is seldom needed for synthetic purposes and where a feel for reactivity can often be gained from every day experiments, it is crucial in radical chemistry to have at least a semiquantitative idea of the rate constants. Indeed, it is the lack of solid kinetic information and the consequent inability to avoid “groping in the dark” that has given radical chemistry its undeserved bad reputation of unwieldiness and unpredictability. Unfortunately, this lingering suspicion will not dissipate soon, largely because of the poor teaching of radical chemistry, both at the undergraduate and graduate levels. Most universities, even top tier ones, do not have full-fledged courses on radicals and limit their teaching to a pitiably few lectures, centered chiefly on the well-behaved chemistry of organostannanes. This gap in the training of chemistry students is regrettable. Those joining industry tend to forfeit the possibilities offered by radical reactions, in part because of the mistaken perception that these will somehow have to involve toxic heavy metal reagents or because of a widespread and surprisingly tenacious belief that radical reactions necessarily pose unacceptable explosion hazards upon scale up. Any inordinately exothermic reaction, whether radical or not, can erupt uncontrollably and, while it is true that fires and most explosions involve radicals, these are generally branched-chain processes that are not the ones used in synthesis. The safe production of many types of polymers on a huge scale for almost a century is the best proof that radical reactions can indeed be tamed, especially when information about the mechanism and reaction rates are available. However, the continued success in the polymer industry did not translate into an increased application of radical reactions for the manufacture of small molecules. Low attendance by industrial chemists and consequent lack of funding resulted, for example, in the discontinuation of the biennial Gordon Research Conference on Radicals and Radical Ions in Chemistry and Biology a decade ago. This is symptomatic and contrasts with the continued interest and rapid expansion in the use of transition-metal-catalyzed transformations. In this respect, a point that is frequently overlooked is that radicalchain processes (and polymerizations) are triggered by a small amount of an initiator, such as a peroxide or a diazo compound, or even a redox system (photolysis and photoredox systems may also be used but are less common in an industrial setting). Although the initiator is not a catalyst, for it is destroyed during the reaction, the overall result is similar: a small quantity of an additive can induce the formation of a large amount of product. Commercial initiators are very inexpensive and can be sacrificed, in contrast to most homogeneous transition-metal catalysts, which are not only expensive but rarely survive intact, and only the metal can be recovered and eventually recycled. There is therefore much to be said in favor of radical-chain processes from an efficiency/cost standpoint and their (underappreciated) potential for the chemical, pharmaceutical, and agrochemical industries. One aspect that often surprises students and newcomers to the field, more attuned to ionic and organometallic chemistry, is that water is one of the best solvents for radical reactions. The O−H bond in water may be considered labile toward heterolysis 1258


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persistent metal-centered free radicals that mediate a family of important reactions known as the Kharasch reactions.26 All these chemistries imply the invisible but crucial operation of the Fischer−Ingold Effect. The Kharasch reaction mediated by copper complexes is the basis of the atom transfer radical polymerization (ATRP), which represents another major, controlled polymerization process for the manufacture of block copolymers. There are thousands of publications and patents dealing with this technology.27 Copper(II) and Ti(III) are also involved in certain radical reactions of diazonium salts, such as the Sandmeyer and Meerwein reactions.28 Most paramagnetic transition-metal salts and complexes are in fact persistent or semipersistent radicals (i.e., they dimerize reversibly), and more and more evidence is emerging pointing to a radical component in many organometallic transformations.29 Such radical steps would involve, for example, the selective capture of a carbon-centered radical by the persistent paramagnetic metal complex, and the intermediate thus obtained then undergoes the usual reductive elimination. This ensures efficiency and high selectivity. The equation in Scheme 3 generalizes the case for various transition-metal

Scheme 4. Key Radical Cascade in the Synthesis of Batrachotoxin

Scheme 5. Key Radical Cyclization in the Synthesis of Azadirachtin

Scheme 3. Possible Operation of the Persistent Radical Effect in the Formation of Organometallic Species

complexes such as Pd(I), Ni(I), Rh(II), Ir(II), etc. Even though not yet widely appreciated by organometallic chemists, the critical role of the Fischer−Ingold Effect in numerous transition-metal-mediated transformations will ultimately become apparent.30 The revival that radical chemistry has witnessed in the last quarter of the 20th Century hinged mostly on the formidable chemistry of stannanes. The review by Baguley and Walton in 1998 is aptly titled “Flight f rom the Tyranny of Tin: The Quest for Practical Radical Sources Free from Metal Encumbrances”.31 The ubiquitous tri-n-butyltin hydride is still used occasionally to solve tricky synthetic problems. One very recent and particularly elegant example is found in the synthesis of batrachotoxin 8 by Du Bois and co-workers.32 The key step where the top right-hand side of the molecule is stitched together is pictured in Scheme 4. The intermolecular addition of stannyl radicals on the terminal alkyne in intermediate 9 is followed by a 6-endo ring-closure and capture of the resulting tertiary radical by the alkynylsilyl appendage.33 The sequence does not end there, for vinylic radical 10 thus formed engages in a relatively rare 1,4-hydrogen atom shift (as opposed to the much more common 1,5-hydrogen atom transfer) to afford finally allylic stannane 11, an ideal stepping stone to batrachotoxin 8. Another example is the key step in Ley’s synthesis of the formidable azadirachtin 12 (Scheme 5).34 The Barton− McCombie deoxygenation of xanthate 13 is followed by concomitant cyclization of the intermediate radical onto the allene to give compound 14. This is a simpler sequence, but it, too, solves a major hurdle in the approach to azadirachtin 12

and further demonstrates the tolerance for many functional groups. The enabling power of stannane chemistry has been both a blessing and a curse. On the one hand, its versatility awakened the synthesis community to the unique potential of radical methods, but on the other, its sheer domination has given credence to the widespread, but incorrect, impression that most of the synthetically useful radical transformations require the use of stannanes. Thus, the combination of the latter misconception with the perceived toxicity of organotin derivatives and the almost unsurmountable purification problems have all but precluded large-scale applications of radical chemistry in the synthesis of medicinal compounds, where strictly heavy-metal-free products are mandatory. The recent surge in the development of radical methods has moved away from organotin reagents and focused more on redox and photoredox processes. This will be apparent in the present ACS Select Virtual Issue, where I was asked to select a total of 24 articles from the publications that appeared over the past two years in Org. Lett. (9 articles), J. Org. Chem. (9 articles), and J. Am. Chem. Soc. (6 articles). Humble apologies are therefore due to all the colleagues and friends whose very worthy work could not be highlighted. A good place to start is the Perspective article by Baran and co-workers.35 In this paper, the authors have succeeded in retracing the history and evolution of radicals and placing their own contribution into context in a very condensed yet clear and readable manner. An early foray into radical chemistry is highlighted by the spectacular, one-step assembly of the two 1259


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by the formation of compound 26 from Barton ester 23 (Scheme 8). The operation of the Fischer−Ingold effect

main structural elements of hapalindole Q, 17, pictured in Scheme 6. Conditions were devised for oxidizing the enolate derived from carvone 15 and adding the resulting radical to the 3-position in indole to give advanced intermediate 16.

Scheme 8. Alliance between Radicals and Organometallics

Scheme 6. Highly Convergent Route to Hapalindole Q

There has been in recent times a strong demand by the pharmaceutical industry for simple methods allowing the latestage modification of promising leads to optimize rapidly the biological profiles.36 Most interesting biologically active substances contain a (hetero)aromatic motif, and radical addition represents an attractive and versatile approach to modify such systems under mild conditions. Baran and his team, concomitantly with the group of Molander (see below), addressed this problem by generating the desired radicals by oxidizing various boronates with silver salts using persulfate as the stoichiometric oxidant. This “borono-Minisci” method, as they called it, failed to produce the electrophilic trifluoromethyl radical. The introduction of fluorinated groups into active ingredients is often highly desirable, and radicals are particularly apt in this respect. The oxidation of sodium triflinate (Langlois’s reagent) with tert-butyl hydroperoxide proved more promising. It was later found that the corresponding zinc triflinates offered significant practical advantages in some cases. The sulfinate variation was extended to the creation and interception of many fluorinated and nonfluorinated radicals. One particularly interesting approach to access sulfonate salts cleverly exploited the powerful Barton decarboxylative rearrangement, which, in the absence of other radical traps, converts a carboxylic acid via its Barton esters 18 into pyridyl sulfide 19 (Scheme 7). Oxidation to the sulfone and cleavage

discussed above (cf. Scheme 3) is almost certainly behind the selective interception of the carbon radical by the nickel complex to give key intermediate 25. Esters of N-hydroxyphthalimide are more practical precursors for such transformations because they are less sensitive to light and less susceptible to hydrolysis. In the conversion of ester 27 into product 28, the intermediate carbon radical is first captured by benzyl acrylate prior to the cross-coupling with the metal complex. The invisible hand of the Fischer−Ingold effect can also be seen in recent work by Shenvi and collaborators,37 where catalysis by a combination of cobalt and nickel is used to couple 4-pentenenitrile to 4-trifluormethyl-iodobenzene 29 to give product 30 (Scheme 9). The process is complex and its Scheme 9. Radicals and Two Metal Complexes

Scheme 7. Direct Functionalization of Heteroarenes

mechanism is not completely clear, but implies probably the initial formation of an organocobalt intermediate 31 by hydrocobaltation of the starting alkene. The C−Co bond is generally quite weak and readily undergoes reversible homolysis. The released radical is then captured, possibly reversibly, by the nickel complex and allowed to partake in a reductive elimination with the aryl component to furnish the observed product. Another ingenious association where the persistent radical effect is operating was devised by Doyle38 and concomitantly by Molander.39 An example from Doyle’s work is outlined in Scheme 10, where chloroindole 34 is converted into tetrahydrofuranyl coupled product 35 in good yield by the combined action of Ni and Ir complexes under irradiation with blue light. Oxidative addition of the Ni complex furnishes LnNiII(Cl)Ar, which is oxidized by the excited IrIII* species to give LnNiIII(Cl)Ar. In accord with earlier observations of Nocera,40 this NiIII species expels upon irradiation a highly reactive chlorine atom that rapidly abstracts hydrogen from the THF solvent. The resulting tetrahydrofuranyl radical cross-couples selectively with LnNiIIAr to give the corresponding NiIII intermediate, which undergoes the expected reductive elimi-

with thiolate liberates the desired sulfinate 20. The remarkable tolerance of this route is illustrated by the conversion of pyridyl boronate 21 into adduct 22 without cleavage of the easily oxidized boronate moiety. This pathway to the target molecule 23 is significantly shorter and vastly more efficient than the previously described route. The work with Barton’s esters led to an interesting observation, namely the possibility of capturing the intermediate carbon radical with an arylnickel complex and inducing a reductive elimination to give the coupled product, as shown 1260


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Scheme 10. Nickel and Iridium in Action

Scheme 12. Synthesis of Trifluoromethyl-Substituted Sultones

nation to release the product and a NiI complex that is reduced back to the initial Ni0 complex by the IrII species created earlier in the sequence. This last operation also regenerates the starting IrIII complex, thus closing both catalytic loops. A somewhat related transformation was reported by Li, Lei and co-workers (Scheme 11).41 The cross-coupling between an

persistent metal-centered radical nature of CuII species and their ability to scavenge other radicals selectively. A single-electron-transfer (SET) from the CuI complex to the highly electrophilic trifluoromethanesulfonyl chloride followed by collapse of the resulting radical anion furnishes cupric complex 41 and trifluoromethyl radical. Capture of the adduct radical by the persistent CuII species gives rise to a transient CuIII intermediate 42, which can now suffer a reductive elimination, leading to sulfonyl chloride 43, regenerating in the process the starting CuI complex. The group of Koike and Akita used a ruthenium(II) complex to produce trifluoromethyl radicals by a one-electron reduction of Umemoto’s reagent 44 in a synthesis of spirooxazolines such as 46, starting from unsaturated amide 45 (Scheme 13).44

Scheme 11. Coupling of Aromatic and Aliphatic Bromides

Scheme 13. Generation and Capture of Trifluoromethyl Radicals aromatic bromide and an aliphatic bromide is also mediated by the cooperative action of nickel and iridium complexes under irradiation by a blue light from a LED source. The intermediacy of radicals was suspected because the process is shut down completely in the presence of TEMPO, but no mechanism is given in the paper. One possible explanation is that both complexes 37 and 38 are formed in the medium. However, because of the very large difference in stability, of the order of 15 kcal/mol,42 between an aromatic and a secondary aliphatic radical, the latter fragments much more easily release a small concentration of cyclopentyl radicals into the medium. The cyclopentyl radicals therefore keep shuttling between the various persistent paramagnetic metallic complexes present in the medium until both the cyclopentyl and the anisyl groups find themselves on the same metal and can therefore undergo reductive elimination to give the cross-coupled product 36. Moreover, because complexes of type 37 fragment more slowly than cyclopentyl complexes 38, the former will be present in a greater concentration and will therefore have a greater chance of intercepting stray cyclopentyl radicals to give preferentially the desired mixed complex 39, from which the heterocoupling product 36 is derived. An unusual sequence proceeding under copper catalysis and irradiation by a green LED light was recently uncovered by the group of Reiser.43 It involves the addition of the elements of trifluoromethanesulfonyl chloride and leads to sultones such as 40 in the case of unsaturated alcohols (Scheme 12). The mechanism depicted in this scheme is a slight variation on the one proposed by the authors, for it takes into account the

Intermediate benzylic radical 47 arising from the addition to the activated styrene type alkene is readily oxidized by electron transfer to [RuIII] (thus regenerating the initial catalyst) or directly to Umemoto’s reagent. Both pathways are possible. In the latter case, the ruthenium catalyst serves to initiate the chain and keep it going in case it is stopped by unwanted side reactions. Overman and co-workers have used the same ruthenium complex to generate tertiary radicals from the corresponding alcohols via their N-hydroxyphthalimido oxalates.45 These are readily prepared by reaction of the alcohol with Nhydroxyphthalimido oxalyl chloride 50, as shown by the synthesis of derivative 51 from alcohol 49 (Scheme 14). NHydroxyphthalimido oxalates are hydrolytically labile and require care in their manipulation, even if they are photochemically more robust in comparison with the related Barton oxalates derived from N-hydroxy-2-thiopyridone.46 1261


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leading to compound 60, no β-scission of the strong C−O bond of the benzoate is observed at the level of adduct radical 62a (X = OBz). This contrasts with what would have happened in the case of an anionic conjugate addition and serves to highlight an important difference between radical and ionic chemistry. The C−Br bond is comparatively much weaker, and the corresponding intermediate 62b (X = Br) readily undergoes elimination of a bromine atom, which then abstracts a hydrogen atom from Hantzsch’s ester 52. Thus, depending on the choice of the acceptor alkene, a simple addition or an addition− elimination sequence can be implemented. The radical chemistry of N-hydroxyphthalimide derivatives, first reported by Okada and co-workers in 1991 (25 years ago!), is proving to be a gold mine.47 The preceding examples are a testimony to the dramatic surge that has swept the field of photoredox catalysis as applied to organic synthesis. This field is not new but has lain dormant for decades. Indeed, more than 90% of the publications related to the subject are posterior to 2010. In an extensive Perspective,48 MacMillan and co-workers retrace the history of photoredox catalysis and detail the contributions of various groups. They also outline the applications of such processes to industry. The use of photochemical reactions in general on a large scale has been hampered by many technical difficulties, but the recent availability of powerful LEDs, which generate constant irradiation and little heat, as well as improvements in flow systems could overcome many of the hurdles and propel photocatalytic processes into the realm of industry. The Princeton team has made extensive contributions in this reemerging area of chemistry. One recent example from the MacMillan laboratory is shown in Scheme 16, where the enantioselective β-cyanophenylation of cyclohexanone, leading to compound 64, has been accomplished.

Scheme 14. Creation of Congested Quaternary Centers

Not unexpectedly, N-hydroxyphthalimido oxalates are easier to reduce than the analogous N-hydroxyphthalimido carboxylates (e.g., 27), as indicated by cyclic voltammetry in acetonitrile (reduction potential −1.14 V and −1.26 V vs SCE, respectively). The carbon radicals generated from either precursor can be captured by an electrophilic alkene. In the present case, a valuable quaternary center is created in the process. Blue light irradiation of oxalate 51 in the presence of the ruthenium catalyst and methyl vinyl ketone as the radical trap and Hantzsch ester 52 as the final hydrogen atom donor results in the high yield formation of addition product 54 (Scheme 14). Oxalate 51 is preferably used in slight excess (1.5 equiv). This sequence comprises many subtle unstated aspects. Thus, the intermediate, electron-rich tertiary radical adds faster to the electrophilic methyl vinyl ketone to give adduct radical 53 than it is reduced by Hantzsch ester 52 or oxidized by [RuIII] species. Adduct radical 53, in contrast, is electrophilic in nature; it cannot be easily oxidized and its addition to a second electrophilic alkene is sluggish because of polarity mismatch. Abstraction of hydrogen atom from Hantzsch’s ester 52 to give the desired product 55 and radical 54 is, however, enhanced by matching polar effects and by a favorable enthalpy of reaction. Finally, stabilized and electron-rich radical 54 is oxidized by the [RuIII] species or by direct electron transfer to the starting oxalate 51 to give first cation 56 then pyridine 57 by loss of a proton. Indeed, it was found that these transformations proceeded in equally good yield in the absence of the ruthenium catalyst, but the reaction time was significantly longer (18 h instead of 2 h). Another example is displayed in Scheme 15, where the methylcyclohexanol derivative 58 is decarboxylatively added separately to olefins 59a and 59b. In the case of the former

Scheme 16. Cyanophenylation of Ketones

In this transformation, where photoredox and organocatalysis have been merged, the proposed mechanism invokes oxidation of the enamine tautomer of the imine derived by condensation of cyclohexanone with chiral, nonracemic amine 63 by SET to an iridium(IV) species, itself generated by oxidation of the excited [IrIII]* complex by the dicyanobenzene. Recombination of the enamine radical 65 with the persistent radical anion 66 leads to intermediate 67, which loses a cyanide molecule to give 68. Hydrolysis finally furnishes the observed product. Photoredox processes based on metal complexes are not limited to generating carbon radicals. Stephenson and his team have used a combination of iridium and palladium complexes to accomplish oxidation of lignin models.49 The ultimate aim is to develop a practical method to add value to a very abundant and cheap biobased material. An example from their work is

Scheme 15. Quaternary Center by Addition−Fragmentation

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portrayed in Scheme 17. Irradiation of the [IrIII] catalyst leads to a long-lived excited [IrIII]* species capable of oxidizing the

Scheme 19. Synthesis of Difluorocarboxylates

Scheme 17. Oxidation of a Lignin Model

[PdII] into a [PdIII] moiety with formation of a lower oxidation state [IrII] complex. The latter is oxidized back to the original [IrIII] catalyst by the persulfate, which itself is cleaved into a sulfate dianion (SO42−) and a strongly oxidizing sulfate radical anion (SO4•−) capable of raising further the oxidation level of the palladium complex into a [PdIV] reagent that finally performs the oxidation of benzylic alcohol 69 into ketone 70. The last step returns the [PdII] catalyst and closes the second catalytic cycle. Knowles and co-workers took advantage of the oxidizing power of a photoexcited [IrIII] complex, Ir(df(CF3)ppy)2(bpy)PF6, to generate nitrogen-centered radicals from anilides, carbanilides, N-arylureas etc., in what they termed protoncoupled charge transfer.50 The examples depicted in Scheme 18

In a Perspective, Kö nig and collaborators review the photocatalytic methods for the oxidation of various anions, such as nitrates, thiocyanates, sulfinates etc., to give the corresponding radicals.52 These species can be employed in different ways, depending on the synthetic purpose. The example selected from their contribution and outlined in Scheme 20 illustrates the addition of a phenylsulfonyl radical to Scheme 20. Synthesis of Unsaturated Sulfones

Scheme 18. Generation and Capture of Nitrogen Radicals

represent two families of products, namely lactams and cyclic carbamates. Thiophenol is the hydrogen atom donor needed to quench the cyclized radical. It is regenerated from the thiyl radical by reduction with the [IrII] species resulting from the earlier step in which the nitrogen-centered radical is formed. This operation gives back the starting [IrIII] complex and closes the catalytic cycle. It is remarkable that oxidation of the substrate can take place in the presence of the thiol, in view of the weaker PhS−H bond in comparison to an N−H bond. It is possible that SET is taking place at the level of the easier to oxidize anion, which is consistent with the need for a base and for the presence an aryl or heteroaryl group on the nitrogen to increase the acidity. Indeed, N-alkyl derivatives are not competent substrates under the present conditions. Nonetheless, this approach is tolerant of numerous functional groups and provides speedy and convenient access to quite complex structures. The agency of an iridium complex was also used by Qing to produce sulfonyl radicals from sulfonyl fluorides.51 The loss of sulfur dioxide is rapid and furnishes a difluoromethoxycarbonyl radical, which can be trapped by an alkene or even a heteroarene, as shown in Scheme 19. In the case of alkenes, the final hydrogen atom transfer is assumed to occur from the solvent, N-methylpyrrolidone (NMP). A very useful difluoroacetate motif can therefore be readily introduced into various structures.

dihydronaphthalene 71 to give vinylsulfone 72 (note that unlike most aliphatic sulfonyl radicals, arylsulfonyl radicals do not extrude sulfur dioxide under common experimental conditions, i.e., excluding pyrolyses).53 Initially, the process was optimized using [Ru(bpy)3]Cl2 as the photoredox catalyst but then switched to the cheaper and equally effective organic dye, eosin Y. In this sequence, irradiation of [eosin Y] generates triplet excited [eosin Y]* following intersystem crossing from the first singlet excited state. This species is easily oxidized by nitrobenzene to give radical cation [eosin Y]•+ and radical anion 73. The former species converts the phenylsulfinate through a SET into the corresponding phenylsulfonyl radical, which readily adds to dihydronaphthalene. It is then assumed that the resulting adduct radical 74 undergoes hydrogen atom abstraction by radical anion 73 to give the observed sulfone 72 and nitrosobenzene. Nitrosobenzene ultimately is completely reduced to aniline. Replacement of the prohibitively expensive ruthenium and iridium catalysts by organic dyes is a trend that is gaining momentum, especially for transformations that could be of interest to the pharmaceutical and agrochemical industries.54 In this respect, Molander and collaborators reported that excited eosin Y is capable by SET of generating the corresponding radical from organic trifluoroborate salts.55 These radicals can 1263


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be captured by various radical traps in synthetically relevant transformations. The examples in Scheme 21 illustrate another

Scheme 23. Silver-Catalyzed Allylation of Carboxylic Acids

Scheme 21. Vinylation and Allylation of Organotrifluoroborates

is, moreover, a significant selectivity in the decarboxylation in that aliphatic carboxylic acids are oxidized faster than aromatic acids and tertiary carboxylic acids faster than secondary or primary. This synthetically useful selectivity is illustrated by the regioselective transformation of dicarboxylic acids 85 and 86 into monofunctionalized derivatives 88 and 89. In a longstanding collaborative effort, the groups of Fagnoni and Ryu exploited the photoredox properties of tetrabutylammonium decatungstate (TBADT) to create and capture acyl radicals.58 The initial idea was to irradiate with UV light a mixture of a cyclopentanone, an electrophilic radical acceptor, and TBADT. Irradiation would generate the aldehyde by a Norrish type I fragmentation of the cyclopentanone, and the excited decatungstate would proceed to abstract the aldehyde hydrogen to give the acyl radical, which would be intercepted by the electrophilic alkene. Unfortunately, the presence of TBADT inhibited the Norrish fragmentation, presumably by absorbing most of the light. The sequence, therefore, had to be performed sequentially by adding the olefinic trap and TBADT to the flask once the formation of the aldehyde was complete. An example starting from norbornanone, which gives rise to aldehyde 90 upon irradiation, is outlined in Scheme 24.

route to vinyl sulfones (78) and an extension to allyl derivatives (79) and to cyanides (80). These various products are generated by addition−fragmentation of the radical derived from trifluoroborate 75 to sulfones 76, 77, and TsCN, respectively, with loss of a sulfonyl radical. In the case of the cyanides, the use of mesitylacridinium (MesAcr+) perchlorate as the photoredox catalyst proved superior to eosin Y. Excited MesAcr+ is a more oxidizing species than the excited eosin Y and is able to form the corresponding radical from a greater range of fluoroborate salts. With an eye on large-scale applications, a Merck group led by DiRocco, in collaboration with the laboratory of Nicewicz at UNC Chapel Hill, successfully designed a series of mesitylacridinium salts with a potency close to that of the iridium complexes.56 The dramatic impact of such structural modifications on the efficacy can be judged by comparing the decarboxylative radical addition of Cbz-protected proline 82 to dimethyl maleate mediated by MesAcr+ 81 and tetramethoxyMesAcr+ 83 (Scheme 22). Under the same reaction conditions, the yield of adduct 84 with the former photoredox catalyst is only 5%, as compared to 86% with the latter.

Scheme 24. Radicals from Aldehydes

Scheme 22. Radical Decarboxylative Alkylation

The generation of radicals by SET is becoming increasingly popular, and the Periodic Table is scoured for potential candidates able to indulge is such chemistry. In a formal synthesis of (±)-triptolide 97, Barriault and his colleagues used a gold complex to produce radical 93 from bromide 92, without reducing the unsaturated lactone (Scheme 25).59 Cyclization furnished tetracyclic compound 94, which was not isolated but exposed to sulfuric acid to induce elimination of methanol. The double bond in the resulting product 95 was isomerized with a ruthenium complex to give the desired intermediate 96, a substance that had previously been converted into triptolide 97. Procter and co-workers recently discovered that addition of a small amount of water to samarium diiodide (Kagan’s reagent) in THF facilitated the reduction of carboxylate derivatives such as simple esters and malonates.60 This combination proved capable of reducing barbiturate-type substrates such as symmetrically substituted compound 98 (Scheme 26).61 The

Li and co-workers exploited the oxidizing power of argentic salts to generate carbon radicals from carboxylic acids and capture them with electrophilic alkenes such as 87 (Scheme 23).57 Persulfate is the stoichiometric oxidant, as indicated by the mechanism pictured in the lower part of the Scheme. The ester group in 87 can be replaced by other electronwithdrawing groups such as a nitrile, and a 5-exo cyclization can be inserted prior to the addition−fragmentation step. There 1264


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tricyclic compound 104 is obtained in a sequence whereby three new C−C bonds and two rings are formed in one operation. The first addition−cyclization furnishes intermediate 105, and ring closure onto the aromatic ring gives rise to cyclohexadienyl radical 106. This easily oxidized species could then evolve into the aromatic product by SET to the diazonium salt, thereby also propagating the radical chain. The lithium iodide serves as an initiator for the system, possibly through the formation of small amounts of the thermally unstable iodoazene (Ar−NN−I). Another application of diazonium salts hails from the laboratory of Heinrich.63 It represents an overall very economical and practical carboamination of an alkene, as illustrated by the example displayed in Scheme 28. The reaction

Scheme 25. Formal Route to Triptolide

Scheme 28. Radical Carboamination of Alkenes

Scheme 26. Samarium Iodide Based Cascade

of diazonium salt 107 and alkene 108 in the presence of sodium carbonate results in the formation of compound 109, which could be converted into the corresponding amine by reduction of the diazo group. Diazoanhydride 110, logically formed upon exposure of diazonium salt 107 to aqueous base, could slowly decompose upon mild heating to generate the corresponding aryl radical and diazenyloxyl radical 111. The former adds to the alkene, and the resulting adduct radical 112 can evolve into diazo product 109 by various routes, which are not mutually exclusive. One is by direct reaction with the starting diazonium salt 107; another, shown here, is by reaction with diazoanhydride 110 to give intermediate 113, which should easily fragment into product 109 and diazenyloxyl radical 111. This species could revert to the diazonium salt 107 by SET and protonation or possibly lose nitrous oxide to furnish directly the aryl radical, even though the driving force for such a process would be expected to be lower than expulsion of molecular nitrogen. Organoboranes are also convenient sources of carboncentered radicals. Oxidation of organoboranes, as discussed above, is one method. Another, extensively investigated by Renaud, consists in attacking the organoboranes with oxygen or nitrogen radicals, which causes homolytic rupture of the C−B bond. In a recent contribution from his laboratory, this approach was combined with the Matteson synthesis to generate and capture monochloroalkyl radicals. Although several synthetically useful methods are available for the production of geminal di- and trihaloalkyl radicals, routes to monohaloalkyl radicals are scarce. Renaud’s approach is illustrated for the case of β-pinene (Scheme 29).64 Hydroboration furnishes borane 114 with a good stereoselectivity, to

generated ketyl radical 99 could be captured in two successive radical cyclizations, leading to product 101 after hydrolysis of intermediate samarium salt 100. In this sequence, five contiguous stereocenters are installed with high stereoselectivity. The exact role of LiBr is still not clear, but its beneficial role was unequivocally established experimentally. It is further interesting to note that the aromatic bromides are not affected under the reaction conditions. Another spectacular cascade was described by Studer, revolving around the generation of an aryl radical via the diazonium salt and its capture by a 1,6-enyne (Scheme 27).62 Thus, starting from enyne 102 and 4-phenoxyaniline 103, Scheme 27. Cascade Starting from a Diazonium Salt

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this species in the medium will therefore be much greater than that of its regioisomer 118b. If the alkene is the limiting reagent, then addition will involve mostly the more stable radical. This is indeed what is observed in practice as demonstrated by the completely regioselective addition to allyl benzoate to give adduct 119. For the same reasons, reaction with a second olefin, allylbenzene, will now proceed on the other side of the ketone to give the more complex compound 120. Finally, reductive removal of both xanthates delivers the sulfur-free keto-ester 121 possessing different chains on either side. This compound can be converted into alkyne 123 by reaction of the corresponding isoxazolinone 122 by nitrosation in the presence of iron sulfate.67 Interestingly, this additive generates nitric oxide in situ and suppresses an unwanted radical side reaction by the persistent radical effect. Overall, one can view bis(xanthate) 117 as the synthetic equivalent of the bis-radical 124, an unknown species that would be devilish if not impossible to generate and manipulate. Iodides can sometimes be made to add to unactivated alkenes. Like xanthates, the exchange of iodine atoms is a very fast process, but the generation of small amounts of molecular iodine or hydrogen iodide can inhibit the radical chain. These problems can often be overcome by the addition of hexabutylditin, which is an excellent scavenger for both species. It can also participate in the initiation or act as a relay within the radical chain itself. Landais and co-workers have used this approach in a 10-step synthesis of (±)-eucophylline 130, an alkaloid isolated in minute amounts from Leuconotis eugenifolius (Scheme 31).68

Scheme 29. Generation and Capture of a Monochloroalkyl Radical

which the Matteson reaction was applied. It was found that unlike ordinary boranes, heating was required to induce migration of the alkyl group from boron to carbon. Chloride 115 was then subjected to the radical allylation using tert-butyl hyponitrite as the initiator to give finally chloride 116 without isolation of the intermediates. Xanthates and related derivatives such as dithioesters and trithiocarbonates have emerged as rather unique precursors of radicals.65 Unlike the Barton−McCombie deoxygenation discussed briefly in the introductory section, the process involves scission of the C−S bond. Used in this manner, xanthates exhibit the remarkable ability to store reactive radicals in a dormant form and thereby significantly enhance their lifetime in a concentrated medium, while at the same time regulating their absolute and relative concentrations. This allows numerous intermolecular additions even to unactivated alkenes by what can be described as a degenerative xanthate addition-transfer. One application is the synthesis of unsymmetrical ketones presented in Scheme 30 from the Zard group.66 Starting from bis(xanthate) 117, both radicals 118a and 118b can be generated. They exist in a rapid equilibrium that favors by far the most stable radical 118a. The concentration of

Scheme 31. Total Synthesis of Eucophylline

Scheme 30. Synthesis of Unsymmetrical Ketones

To access key bicyclic intermediate 129, Landais used a three-component radical cascade to form its precursor 128, whereby the radical generated from iodoacetate 125 adds to olefin 126, and the resulting nucleophilic adduct radical is captured by the electrophilic sulfonyloxime 127 in an addition−fragmentation with elimination of a sulfonyl radical and formation of the important quaternary center. The last transformation is based on the seminal work of Kim.69 One of the side reactions that sometimes plagues radical transformations is internal hydrogen atom transfer (HAT) which causes translocation of the radical center to another site in the molecule. The most common is the 1,5-HAT because of a generally favorable geometry. Mastery of the HAT process can nonetheless prove to be a tremendous asset in synthetic planning.70 The atom or functional group destined to act as the precursor of the radical can thus be placed on the more accessible corner of the molecule and use HAT to transfer the radical center to the desired but less accessible part. Such a strategy was employed to remarkable effect by Sammis’ group 1266


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hydrogen atom. The selective monofunctionalization of (+)-sclareolide 138 is a striking example of the synthetic potential of this method. Furthermore, the xanthate group introduced in product 139 represents an unusually versatile stepping stone to a large assortment of functional groups. It can, for example, be replaced by deuterium (140a); by an alcohol (140b), which can be oxidized to the ketone; by an azide (140c), which can be reduced to the amine; by a thiol (140d) or a trifluoromethyl sulfide (140e); or by an allyl (140f) or a vinyl group (140g), which can be cleaved by ozonolysis to furnish the corresponding homologous aldehydes. Radical chemistry offers many of the properties desired by synthetic organic chemists. The experimental conditions are generally neutral and mild; the reactions are compatible with numerous functional groups, especially polar entities such as alcohols, carboxylic acids, etc., that often require protection with other chemistries; there is little tendency for rearrangements or β-eliminations, unlike the case with cationic and anionic intermediates, respectively; even though radicals can be reactive species, the reaction rates span several order of magnitude, and a remarkable chemoselectivity can be achieved. The critical role of radical intermediates and persistent paramagnetic metal complexes in transition-metal-based transformations is increasingly apparent. The controlling hand of the Fischer−Ingold will surely become less invisible and better appreciated in the not too distant future. It is hoped that this ACS Select Virtual Issue dedicated to radical reactions will contribute a little bit to increasing the awareness of academic and industrial synthetic chemists to their vast potential and encourage a better teaching of radical chemistry in universities.

in the construction of the eastern portion of (−)-amphidinolide K (Scheme 32).71 Scheme 32. Hydrogen Atom Transfer Route to Tetrahydrofurans

The sequence starts from N-alkoxy-phthalimide 131. Attack by stannyl radicals gives rise to highly reactive alkoxy radical 133 by rupture of the relatively weak N−O bond. The ensuing thermodynamically favored and fast HAT is followed by ring closure on the alkyne to furnish the desired tetrahydrofuranyl motif 132 with very good control of stereoselectivity. Clearly, generating the radical directly on the site where it is actually needed by placing a suitable substituent on the starred carbon in 133 would have been synthetically much more challenging. It is also interesting to note that the HAT process is much faster than the unwanted addition of the alkoxy radical to the alkyne to give vinyl radical 134. In contrast to the intramolecular HAT, where regioselectivity and efficiency are dictated by geometrical constraints and favorable entropic factors, intermolecular HAT is much more difficult to accomplish. One impressive solution to this fundamental problem has emerged from the laboratory of Alexanian, who conceived of reagent 136 as an entity capable of performing regioselective C−H activation with very reasonable efficiency, even on complex structures (Scheme 33). This compound is readily made on decagram scale from simple, inexpensive chemicals and is shelf-stable. The underlying reasoning is to take advantage of the electrophilicity and bulk of the corresponding amidyl radical 137 to pluck off the most sterically accessible and electron-rich

Samir Z. Zard

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Laboratoire de Synthèse Organique, UMR 7652 CNRS/Ecole Polytechnique

AUTHOR INFORMATION

Notes

Views expressed in this editorial are those of the author and not necessarily the views of the ACS.

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DEDICATION Next year will mark the centenary of the birth of Sir Derek H. R. Barton. I should like to dedicate this article with respect and affection to his memory. My debt to him is unredeemable.

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REFERENCES

(1) The original anonymous limerick goes as follows:

Scheme 33. Regioselective C−H Activation

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