& Hydrogen-Atom Transfer

1,n-Hydrogen-Atom Transfer (HAT) Reactions in Which n¼6 5:An Updated Inventory

Malek Nechab,*[a] Shovan Mondal,[b] and Mich�le P. Bertrand*[a]

Chem. Eur. J. 2014, 20, 16034 – 16059 � 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim16034

ReviewDOI: 10.1002/chem.201403951

Abstract: Hydrogen-atom transfer (HAT) counts amongst themost widely investigated routes to carbon-centered radicals.Intramolecular processes involving 1,5-HAT are widespreadto promote regioselective radical “C�H activation”. The aim

of this review is to draw up a comprehensive inventory ofthe less commonly encountered 1,n-radical translocations(n¼6 5) with the aim to update this topic with the mostrecent relevant data.

1. Introduction

Hydrogen-atom abstraction reactions have long been recog-nized as a versatile tool to perform C�H activation. Historically,early works on rearrangements, such as Hofmann–Lçffler–Frey-tag reaction[1] and Barton’s nitrite photolysis,[2] have pointedthe interest of regioselective intramolecular hydrogen-atomtransfers (intra-HAT) for remote C�H functionalization. Sincethen, 1,5-hydrogen-atom transfers have been abundantly in-vestigated and numerous reviews or book chapters have beendedicated to this topic.[3-6] This progress, accomplished thanksto the fundamental knowledge of these radical reactions, hasstimulated the development of elegant radical cascades for theconstruction of complex molecules. The peculiarity of thisreview is to focus exclusively on the less common 1,n-HAT re-actions with the aim to highlight their specificity, their synthet-ic potential, and their involvement in some biomimetic mecha-nisms. The following sections are organized according to theposition of the abstracted hydrogen atom, that is, 1,n-HAT withn = 4,6,7,8, and so forth, without necessarily taking into ac-count the nature of the abstracting radical. Attention will bealso drawn to intra-HAT reactions in biradicals.

2. Theoretical background and kinetic data

HAT reactions are controlled by different parameters, amongstwhich the enthalpy of the reaction is crucial. Most efficientHAT reactions are exothermic irreversible processes with earlytransition states and, thus, their activation energy is also sensi-tive to polar effects. They involve mainly heteroatom-centeredradicals (X = O, N, less frequently S) or vinyl and aryl radicals(X = sp2 C), but exothermic HAT to alkyl radicals are alsoknown.[7] Quantum chemistry and force-field-based calculationshave been used to model HAT.[8–11] It is currently accepted thatthe ideal arrangement of the three atoms involved in the tran-sition state of intermolecular HAT is linear. However, small dis-tortion from linearity (X-H-C angle between 145–1808) wasshown to have little energetic cost. Typically, the distance be-

tween the radical center and the hydrogen atom to be ab-stracted should be �3 �.

With regard to intramolecular HAT, the deviation from theideal quasi-linear atoms arrangement induces necessarilya cost in term of activation energy, which depends on the sizeof the ring in the cyclic transition structure (Scheme 1, com-

pounds 1.1 and 1.2.[8] Radical translocation implying 1,2- or1,3-hydrogen-atom migration have highly strained distortedtransition structures, and relevant examples are ratherscarce.[9, 12] They have little synthetic value; they are mainly rel-evant to biology and pyrolysis. A few examples of 1,4-HAT ofsynthetic value are known, but as discussed below, they dis-play very special features.

It is well established that, even though their 6-endo-tet tran-sition state is formally unfavorable according to Baldwinrules,[13] 1,5-HAT are the most favored processes because thesix-membered transition structure can readily accommodatea C-H-X angle close to 1808. In spite of theoretical calculationspredicting that 1,5-HAT are enthalpically slightly disfavoredcompared to 1,6-HAT, the latter are less frequently encoun-tered than the former. Entropic factors are important in con-trolling the preference for six-membered over seven-mem-bered transition states. As illustrated later on, when both en-thalpic and geometric factors are favorable, the 1,6-HAT modecompetes with the 1,5-mode. It can even become the uniquefate of the abstracting radical species. Even though the ideallinear geometry can formally be reached more easily for 1,n-HAT when n>6, the entropic penalty makes them ratherscarce.

A few rate constants for unequivocal or competitive intra-HAT processes are given in Figure 1.[14–16] These data are repre-sentative of a few situations in which 1,n-HAT are enthalpically

Scheme 1. General reaction profile of 1,n-HAT.

[a] Prof. M. Nechab, Prof. M. P. BertrandAix-Marseille Universit�CNRS, Institut de Chimie Radicalaire UMR727313390 Marseille (France)E-mail : malek.nechab@univ-amu.fr

michele.bertrand@univ-amu.fr

[b] Dr. S. MondalDepartment of ChemistryVisva Bharati, Santiniketan, BirbhumWest Bengal 731235 (India)

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favored. The rate constant increases with the exothermicity.However, entropy is likely to be important and parameters,such as the number of hydrogen atoms available at each site,also influence the kinetics.

3. 1,4-Hydrogen-atom transfer

The mechanistic investigation of 1,4-HAT has drawn the atten-tion of several research groups. The decay of 2,4,6-di-tert-butyl-phenyl radical 2.1 through 1,4-HAT to give 3,5-di-tert-butylneo-phyl radical 2.2 has been studied by ESR by Ingold and co-workers (Scheme 2 A).[17] It was established from kinetic studiesat low temperature and kinetic isotope effects that this exo-thermic rearrangement involved quantum mechanical tunnel-ing.

Exothermicity was questioned as the driving force of the re-arrangement of b-alkylthioalkyl radicals to a-alkylthioalkyl radi-cals, but no experimental evidence was found by Roberts to

support 1,4-HAT in these systems.[18] The data were rationalizedin term of stabilization of alkyl radicals by the neighboringsulfur atom associated to polar effect.

ESR evidence was given for the rearrangement of vinyl radi-cal 2.3 into a-vinylthialkyl radical 2.4.[19] The driving force ofthis 1,4-hydrogen-atom abstraction was likely to be the conju-gative stabilization of the new radical center due to its capto-dative nature. The rearrangement did not proceed in the ab-sence of the carboxylic acid function (Scheme 2 B).

Mich�le P. Bertrand graduated from theUniversity of Aix-Marseille (France) in 1966.She defended her Ph.D. in 1969 under thesupervision of Professor J.-M. Surzur. Shecontinued carrying out her researches atMarseilles where she received the “Doctorates Sciences” degree in 1975 for her work onalkoxyl radicals. She was appointed as assis-tant Professor in 1969 at the University of Aix-Marseille, where she became full Professor inorganic chemistry a few years later. She wasawarded the prize of the organic chemistrydivision of the French Society of Chemistry in2001. Her research area is centered on radicalchemistry and synthesis. During the last ten years, her group, which is now partof the Institute of Radical Chemistry (ICR, UMR 7273), has contributed to: sulfur-centered radicals and bioconversions, conjugate radical additions mediated bydialkylzincs, memory of chirality in enediyne cascade rearrangements, andmesoporous material confinement effects on free-radical reactivity.

Shovan Mondal received his B.Sc. degree fromthe Burdwan University (India) in 2001 andM.Sc. degree from the Visva-Bharati Universityin 2003 with a brilliant academic record. Heachieved his Ph.D. degree from the KalyaniUniversity in 2010 under the supervision ofProfessor K. C. Majumdar. He carried outpostdoctoral research work (2011–2012) inAix-Marseille University, Marseille (France) withDr. Malek Nechab and Prof. Michele Bertrand.Dr. Mondal is now working as an assistantprofessor (DST-Inspire Faculty) in Visva-BharatiUniversity, Santiniketan (India). His researchinterests surround asymmetric synthesis withmemory of chirality (especially in enediyne rearrangement), synthesis ofbiological active heterocyclic compounds and theoretical chemistry.

Malek Nechab studied chemistry at Paris 12University (France) and graduated in 2003. Hethen joined Jacques Einhorn’s group at Gre-noble University and received his Ph.D. in 2006.He worked on novel C2-symmetric and axiallychiral N-hydroxyphtalimides as catalysts forenantioselective oxidations. This work hasbeen recognized with an award from the“Soci�t� Chimique de France” (Prix de Th�seFournier). He moved to Marseille as a CNRSpostdoctoral fellow in G�rard Gil’s and MicheleBertrand’s groups, where he worked ondynamic kinetic resolution of amines. He wasappointed as assistant professor in 2007 atMarseille. His current research interests include asymmetric synthesis, memory ofchirality, and chirality transfer in radical and polar cascade reactions.

Figure 1. Rate constants for some specific 1,n-HAT.

Scheme 2. Representative examples of 1,4-HAT.

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3.1. 1,4-HAT in sterically constrained systems

Reactions involving 1,4-translocations on a preparative scaleare rather scarce; they are often mentioned as unexpectedside processes.[11, 20] As an example Crich et al. have observedcompetitive 1,4-HAT while exploring radical routes based on1,5-HAT to invert a- to b-pyranosides.[21] The reaction of acetal3.1 (1:1 mixture of diastereomers) with tributyltin hydride inthe presence of azobisisobutyronitrile (AIBN) in refluxing ben-zene led, after workup with silicagel, to four products, that is,the expected b-mannoside 3.5, the a-mannoside 3.7, the a-glucoside 3.8, and the ketone 3.9 (Scheme 3).

Deuterium-labeling experiments demonstrated that 3.5 de-rived from 1,5-HAT followed by axial hydrogen-atom transferfrom tin hydride, whereas 3.8 and 3.9 derived from 1,4-HAT viaradical 3.6. Compound 3.7 was formed from the direct reduc-tion of radical 3.2 by Bu3SnH.

The glucopyranoside isomer 3.10 led exclusively to ketone3.9 by means of tandem 1,4-HAT/b-scission—no b-glucosidewas detected. In this system, the hydrogen atoms accessible to1,5- and 1,4-HAT are both equatorial, no stereoelectronic effectfavors one process over the other. It was suggested that the ri-gidity of the chair-like conformation of the pyranose ring wasresponsible for the increased rate constant of 1,4-HAT.

In the following, 1,4-HAT processes favored by the geometryof sterically constrained systems are discussed. In these sys-tems the intra-HAT is not only enthalpically favored, but alsothe geometry of the radical intermediate brings the radicalcenter and the hydrogen atom to be abstracted in close vicini-ty.

Hart and co-workers observed such a rearrangement duringtheir investigation of an approach to the oxindole moiety ofgelsemine based on the cyclization.of an aryl radical.[22] Thetributyltin hydride promoted cyclization of aryl bromide 4.1led to oxindole 4.5 in 46 % yield as the major product(Scheme 4).

Malacria et al. have developed a highly successful cascadereaction involving 1,4-HAT. In this process, using the temporaryconnection of a silicon-containing linker, the conformationallyand enthalpically favored 1,4-HAT step follows the 5-exo-dig

cyclization (Scheme 5).[23] This leads to the formation of thetransient vinyl radical 5.2 from 5.1. In the next step, stereoelec-tronic effects favors the chemoselective 1,4-abstraction of theaxial hydrogen in the a-position relative to the oxygen atom,which proceeds at the expense of 1,5-H transfer from the axialmethyl group. The main drawback of the strategy was the for-mation of the meso-reduced compound 5.6 a (E = H) from theC2-symmetrical acetal. To overcome this problem, the selectivetrapping of the six-membered ring dioxolanyl radical inter-mediate 5.4 by activated alkenes was added to the sequence.

As exemplified in Scheme 5, in the presence of a 15-foldexcess of acrylonitrile and after cleavage of the O�Si bondwith MeLi, the reaction afforded 5.6 b in 56 % isolated yield asa single diastereomer from (S,S)-5.1. Alternatively, upon desily-lation and subsequent ketal hydrolysis, 5.5 b was converted tothe enantiopure triol 5.7 b with a total control of the contigu-ous stereocenters of the triad. The authors have noted that(R,S)-5.1 (the meso starting material) displayed less diastereose-lectivity than (S,S)- 5.1.

Zard et al. have been interested in the total synthesis of (�)-dendrobine. Their first strategy was based on the introductionof the key stereogenic centers via the cyclization of a nitrogen-

Scheme 3. 1,4-HAT competitive pathway in the synthesis of b-mannosides.

Scheme 4. Tandem 5-exo ring closure/1,4-HAT in Hart’s approach to gelse-mine.

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centered radical followed by Pauson–Khand reaction. They in-vestigated the Ni–AcOH mediated cyclization of a-perchloroa-cetamides as a potential alternative to the Co-mediated ringclosure for the construction of the pyrrolidine unit.[24] This ledthe authors to investigate the reactivity of model amide 6.1,which did not undergo the expected 5-exo-ring closure, but in-stead afforded enamide 6.4 in 81 % yield (Scheme 6).[25] The

latter arose from an unanticipated 1,4-HAT, which led to the al-lylic radical 6.3. This pathway, likely to be exothermic due tothe stabilization of radical 6.3 by both the double bond andthe adjacent nitrogen lone pair, is faster than the competing 5-exo cyclization onto the sterically hindered alkene. The last ele-mentary step consists in the trapping of the delocalized allylicradical by diphenyl diselenide at the less hindered position togive 6.4 in high yield. In all likelihood, it is the preferred con-formation around the N�CH bond that governs the rates ofthe two competitive pathways.

We speculate that, althoughhindered, the 5-exo ring closurewould be an available route forthe less favored conformer ofradical 6.2 (conformer b). Con-versely, hydrogen abstraction ismore plausible from the mostfavored conformer 6.2 a. Theproposed s-cis conformation ofthe (O)C-N amide bond mightaccount for the absence of 1,4-HAT from the methylene of thebenzyl group.

Radical translocation accord-ing to 1,4-HAT in closely relatedsystems was rationalized by DFTcalculations.[26] Products 7.3 a

and b resulting from tandem 1,4-HAT/5-exo cyclization wereformed from trichloroacetamides 7.1 a and b, after inter-HATfrom tris(trimethylsilyl)silane (TTMSS) and complete reductionof the remaining chlorine atoms. They were isolated togetherwith products 7.2 a and b expected from direct 6-exo-ring clo-sure (Scheme 7 A and B). Conversely, no translocation productwas detected from the open-chain acetamide 7.1 c, which ledto pyridone 7.2 c through 6-exo-ring closure (Scheme 7 C).Again, the cyclohexenyl moiety seems to be mandatory forthis unexpected outcome to be observed.

According to DFT calculations, Scheme 8 summarizes thetwo competitive pathways. The chlorinated a-carbamoyl radi-cal is generated in the conformation 8.1 a from 7.1 a. Rotationaround the amide C�N bond via transition structure TS1 leadsto conformer 8.2 a, which, after inversion of the six-memberedring (via TS2), gives rise to the conformer 8.3 a, which is moreprone to undergo 6-exo cyclization. The latter affords radical8.4 a (via TS3), which is a precursor of 7.2 a. Alternatively, 8.1 a

Scheme 5. 1,4-HAT in the synthesis of enantiopure 1,2,3-triol 5.7.

Scheme 6. Reactivity of trichloroacetamide 6.1. Speculative conformationalrationale for the competition between1,4-HAT and 5-exo cyclization.

Scheme 7. Compared reactivity of amides 7.1 a,b,c.

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can undergo 1,4-HAT (via TS4) to form radical 8.5 a. Inversionof the chair and rotation around the CH�N bond (via TS5)leads to 8.6 a, which undergoes 5-exo ring closure to radical8.7 a (via TS6), which in turn eventually affords 7.3 a.

It is worth noting that both motions are faster than rotationaround the N�C· bond, which has a p-character due to the rad-ical stabilization by the nitrogen lone pair. The cyclization of8.1 a proceeds with memory of chirality via the conformation-ally chiral radical 8.5 a (other examples will be mentioned lateron). Comparing the energetic barriers of both pathways showsthat in the case of 7.1 a, the formation of the azabicyclono-nane framework is favored by 0.9 kcal mol�1 over that of thenormorphane skeleton. The situation is reversed in the case of7.1 b. In the case of the acyclic structure 7.1 c (Scheme 7 C), theactivation barrier to 1,4-HAT from the corresponding a-carba-moyl radical was calculated higher by 1.1 kcal mol�1 than thatof the 6-exo ring closure.

On the grounds of DFT calculations of its activation energy,an intramolecular hydrogen-atom migration toward a nitro-gen-centered radical intermediate was proposed for the rear-rangement of trimethyl-susbstituted N-chlorohydantoins intothe corresponding chloromethyl hydantoins.[27]

3.2. 1,4-HAT in photochemical reactions

Photoexcited ketones are long known to undergo hydrogen-atom abstraction to generate carbon-centered radicals.[28] Nor-rish-type reactions have foundnumerous valuable syntheticapplications. The following ex-amples illustrate the occurrenceof 1,4-HAT subsequent to Nor-rish I processes.

As shown in Scheme 9, in itsexcited state, ketone 9.1 leadsto biradical 9.2, by a-cleavage.Disproportionation of the latterthrough 1,4-HAT, leads to theunsaturated cyclopentenylframework bearing two cis-vici-nal aldehyde functions. The re-

action led to bicycle 9.3 upon acidic workup in ethanol. Thiskey synthon was then transformed into (�)-specionin.[29] Insuch a case there is virtually no activation barrier to the hydro-gen-atom migration as the process is strongly exothermic, theC�H bond being strongly weakened by the overlap of thes*(C�H) orbital with the adjacent mono-occupied orbital.

Dake and co-workers have exploited an analogous strategyto prepare ketenes 10.3 a and b, which are key precursors ofterpenic natural products (Scheme 10).[30] As in the precedingexample, the Norrish type I fragmentation is followed by 1,4-hydrogen translocation. The OTBS derivative 10.3 a (TBS = tert-butyldimethylsilyl) was used in the synthesis of 1,22-dihydroxy-

Scheme 8. Competition between 1.4-HAT and 6-exo ring closure in the case of trichoroacetamides 7.1 a (DE in kcal mol�1).

Scheme 9. Synthesis of (�)-specionin precursor through Norrish I fragmenta-tion and 1,4-HAT.

Scheme 10. Synthetic approach to 1,22-dihydroxynitianes and fusicoccane A–B ring system.

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nitianes, whereas the protected diol 10.3 b was used to buildthe fusicoccan A–B ring system.

Wagner has reported that a photoinduced 1,4-HAT was in-volved in the formation of cyclopropanol 11.2 a from propio-phenone 11.1 a, in which the HAT was activated by the pres-ence of an electron-rich b-phenyl group (Scheme 11 A).[31] In an

earlier work, the same author had evidenced from isotopic-la-beling experiments that the 1,5-biradical resulting from theNorrish II rearrangement of b-ethoxypropiophenone under-went enolization through 1,4-HAT to the exclusion of any 1,6-HAT.[32]

The Norrish–Yang cyclization has also been used to prepare2-aminocyclopropanols from b-aminoketones.[33] The formationof cyclopropanol is far less documented than the formation ofcyclobutanols or cyclopentanols.[34] Weigel has reported one ofthe earliest examples of tandem 1,4-HAT/biradical diastereose-lective recombination likely to proceed with memory of chirali-ty.[33a] The authors mentioned that the photocyclization ofenantiopure benzophenone 11.1 b led to only one out of thefour possible stereoisomers of aminocyclopropanol 11.2 b. Itwas assumed that the 1,3-hydroxylated biradical intermediate11.3 b collapsed so rapidly that any rotation around theC�C* pivot was prevented (Scheme 11 B).

Memory of chirality (MOC)[35] in photochemical intramolecu-lar hydrogen-atom abstraction was also explored from excitedthiocarbonyl derivatives.[36, 37] Sakamoto et al. reported the pho-tochemical asymmetric synthesis of stereogenic tetrasubstitut-ed carbon atoms, based on 1,4-hydrogen-atom migration fromthe singlet excited state of the thioimide group.[38] Compoundspossessing a tetrasubstituted stereocenter like 12.4 wereformed from the two-step Norrish–Yang reaction that proceedswith memory of chirality (Scheme 12). High enantiomeric ex-cesses were reached both in toluene and in the solid state.The high memory effect was explained by the fact that the re-combination of the short-lived diradical is much faster thanthe racemization of the conformationally chiral intermediate,which would necessitate rotation around the C�N bond at the

radical site in intermediate 12.2. In other words, it is the com-paratively high barrier to rotation around the C�N bond thatpreserves the dynamic chirality during the course of the re-combination. This assumption was confirmed by performingthe reaction in the presence of a triplet sensitizer. Under theseconditions, the photoreaction was unsuccessful, which clearlyindicated the involvement of a singlet biradical in the mecha-nism. The short lifetime of the singlet excited state, which pre-cludes rotation around the C�N pivot, explains the high enan-tioselectivity. The control of the second stereocenter does notmatter as it is destroyed during the ring-opening step.

The authors have extended this methodology to the synthe-sis of optically active b-lactams through 1,5-HAT.[39] Giese et al.had previously reported the synthesis of enantiopure pyrroli-dines involving 1,6-HAT from alanine derivatives using MOCstrategy. This work will be discussed in the Section 4.1.2.

Mikami and co-workers have investigated the photochemicalrearrangement of Baylis–Hilman adducts like hydroxymethyle-nones 13.1. In their first report, these authors demonstratedthat 1,4-HAT was operating in the transformation of 13.1 intothe 1,4-dicarbonyl compound 13.4 (Scheme 13). Crossover ex-periments and deuterium labeling confirmed that the reactionproceeded in an intramolecular fashion.[40] On the basis ofthese results, they expended the reaction to substrates leadingto furans,[41] cyclopentenes,[42] and seven-membered 1,4-dike-tones.[43]

The same authors have investigated the potential of the re-action regarding the enantiospecific desymmetrization of theC2-symmetrical dihydroxytrimethylenemethane ((HO)2-TMM) in-

Scheme 11. Diastereo- and enantioselective synthesis of aminocyclopropa-nols.

Scheme 12. MOC in tandem 1,4-HAT/recombination from excited thiocar-bonyl groups.

Scheme 13. Photochemical rearrangement of Baylis–Hilman adducts to 1,4-dicarbonyl compounds.

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termediate 14.3, in the presence of the cumulative effects ofa C2-symmetrical chiral controller and a chiral supercage, thatis, g-cyclodextrin (g-CD).[44] The chiral recognition throughtriple binding of (S,S)-diphenylethylenediamine (DPEN) withthe substrate in g-CD cage are encouraging, as 80 % ee and45 % yield were observed (Scheme 14).

The methylated vinylogous substrate 15.1 led to preferentialfive-membered ring closure from the intermediate biradical15.2. The reaction afforded cyclopentenol 15.3 in 63 % yield(Scheme 15).[43]

It is worth mentioning that N-allyl thiobenzamides also un-dergo photostimulated 1,4-HAT, but the pyrroles resulting fromsubsequent recombination through five-membered-ring clo-sure are minor products in this reaction (5–14 % yield).[45] As anexample, the irradiation of 16.1 was shown to give rise pre-dominantly to tandem 1,4/1,6-HAT. As shown in Scheme 16,this led to 16.3 as the major product from the isomerization ofthe double bond by means oftwo successive HAT. The minorpyrrole derivative 16.4 wasformed from the recombinationof diradical 16.2 followed byH2S elimination.

3.3. Miscellaneous reactions

Vinylidene cyclopropanes oftype 17.2 are available in highyield through radical addition ofdiphenyl diselenide toallenylcyclopropanes 17.1(Scheme 17).[46] The involvement

of 1,4-HAT in the thermal rearrangement of vinylbicyclo-[3.1.0]hexanes was demonstrated by isotopic labeling. As ex-emplified with the labeled compound, 1,4-deuterium atomtransfer occurring in the preferred conformer 17.4 of the birad-ical intermediate could rationalize the high yielding synthesisof 17.6. Internal 1,4-H/D migration leads to radical 17.5, that is,ultimately to 17.6 when R’= Ar. According to the authors,when R’= Me, the rearranged biradical would undergo an ad-ditional 1,3-hydrogen-atom migration leading to 17.7.

The formation of a-methylene lactams in the radical carbon-ylation of w-alkylnylamines was rationalized according to thesophisticated cascade shown in Scheme 18.[47] The addition oftributylstannyl radical to the terminal triple bond in 18.1 leadsto the vinyl radical 18.2, which is trapped by carbon monoxideto give the a-ketenyl radical 18.3. Subsequent cyclizationthrough nucleophilic addition of the amino group to the car-bonyl gives rise to the zwitterionic intermediate 18.4. Com-pound 18.4 undergoes proton transfer followed by 1,4-HAT toform the enoxyl radical 18.6, which releases tributyltin radicalthrough b-fragmentation to form 18.7. Part of this a-methyl-ene lactam originates from protodestannylation of 18.8 uponworkup. Intermolecular abstraction of the enol hydrogen atomis likely to explain the formation of 18.8. Trace amount of thesaturated stannylated lactam resulting from the reduction of18.5 by tributyltin hydride was also detected. The scope of thereaction was investigated as regard to the lactam ring size andthe synthesis of fused bicyclic lactams. Overall yields varyingbetween 52 to 71 % were observed.

It is worth noting that a completely different outcome ofradical 18.3 occurs when the nitrogen atom is prone to under-

Scheme 14. Desymmetrization of (HO)2–TMM intermediate.

Scheme 15. Photochemical rearrangement of methyl ether 15.1 to cyclopen-tene derivative 15.3.

Scheme 16. Tandem 1,4/1,6-HAT in the photolysis of N-allylated thiobenza-mides.

Scheme 17. Thermal rearrangement of vinylbicyclo[3.1.0]hexanes.

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go a direct intramolecular SH2 reaction, which releases a stabi-lized carbon-centered radical such as the phenethyl radical(formation of 18.9).

Gans�uer has recently reported a sustainable procedure forthe radical reduction of epoxides using a silane as stoichiomet-ric reducing agent instead of stoichiometric Zn or Mn, and 1,4-cyclohexadiene.[48] As summarized in Scheme 19, the method-

ology is based on the in situformation of the TiIII hydride19.1. The reductive epoxidering opening leads to the TiIV

alkoxide 19.3, which undergoes1,4-HAT leading to 19.4. Radical19.4 then reacts with the silanethrough s-bond metathesis toregenerate the catalyst and re-lease the alkoxysilane 19.5,which is hydrolyzed uponworkup.

As exemplified in Scheme 20,by the comparative results ofthe reduction of the cyclohex-ene derivative 20.1 from twodifferent methodologies, due tothe internal reduction of thecarbon-centered radical, thesilane-mediated procedure ishighly diastereoselective. Cou-

pled to the diastereoselectivity, the sustainable character relat-ed to the use of nontoxic silanes as stoichiometric reducingagents confers a high added value to this method.

4. 1,6-Hydrogen-atom transfer

As mentioned above, 1,6-HAT is an enthalpically favored reac-tion, which can occur readily and be synthetically useful, pro-vided there is no possibility for 1,5-HAT to compete. Even inthis event, the subtle interplay of enthalpy and geometry inrigid systems can tilt the balance in favor of 1,6-HAT. Due tothe number of relevant examples their discussion is organizedin this section according to the nature of the abstracting spe-cies.

4.1. 1,6-HAT involving heteroatom-centered radicals

4.1.1. Alkoxy and aminyl radicals

Most examples in this series are related to oxidative transfor-mation of alcohols and amines (or amides). As regard to the re-arrangement of alkoxy radicals, both lead tetraacetate[49] andhypervalent iodine are efficient to promote the synthesis oftetrahydropyranic derivatives from alcohols via hypoiodites in-termediates.[50]

Su�rez clearly demonstrated by deuterium labeling that nocompetitive 1,5-HAT interfered in the transformation of 26-hy-droxy-furostan 21.1 a into 21.2 a mediated with Pb(OAc)4/I2

(Scheme 21 A). The stabilization of the a alkoxy carbon-cen-tered radical favors 1,6- over 1,5-HAT process. An additionallowering of the activation barrier by polar effects is plausible,as the electrophilic alkoxy radical generates a more nucleophil-ic radical through 1,6-HAT. The overall sequence implies thecascade combination of oxidation/1,6-HAT/oxidation (eitherdirect or via iodine atom transfer).[51]

Scheme 18. 1,4-HAT in the radical carbonylation of w-alkylnylamine.

Scheme 19. Mechanism of the catalytic titanocene-mediated reduction ofepoxides.

Scheme 20. Evidence for 1,4-HAT-induced diastereoselectivity.

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A similar trend was observed in the N-iodosuccinimide-pro-moted oxidative cyclization of monosilylated 1,5-dihydroxypen-tane (the ratio of 1,6- to 1,5-HAT was 60:7 in this case).[52]

Conversely, no troublesome competition arose from 1,5-HATin the synthesis of cyclic ether 21.2 b from g-hydroxy ether21.1 a (Scheme 21 B).[53]

An impressive contribution to this topic is due to Su�rezand his group work.[54] Carbohydrates derivatives led to a veryaccurate insight of the parameters influencing the regioselec-tivity of these oxidative cyclizations. Oxygen- and nitrogen-centered radicals generated by the action of hypervalentiodine (PhI(OAc)2, DIB) were involved in elegant cascades initi-ated by intra-HAT. The results obtained in the series of 3,7-an-hydro-2-deoxyoctitols demonstrated that slight enthalpic ef-fects and (or) polar effects could completely change the regio-selectivity of intra-HAT.[55] As exemplified in Scheme 22, the re-placement of the methoxy group by an acetoxy group increas-es the BDE of the C�H bond at C4; as indicative values, it canbe noted that the C�H bond is stronger by 1.4 kcal mol�1 inCH3C(O)OCH2�H than in CH3OCH2�H.[56] At the same time, theincoming radical at C4 becomes less nucleophilic. The reactionof the alkoxy radical switches from 1,5-HAT leading to radical22.3 a, to 1,6-HAT leading to radical 22.5 b. The overall yield of1,6-HAT also depends on the b-oxygen effect, that is, the effectof the substituents at C6 and C8, which is likely to retard thehydrogen abstraction from C7.

The activation of 1,6-HAT due to the presence of the adja-cent oxygen atom, was applied to the regio- and diastereose-lective synthesis of C-ketosides by allylation of the anomericposition.[57] Under classical conditions the N-alkoxyphthalimide

derivative 23.1, used as the alkoxy radical precursor, led to23.2 by reacting with allyltributyltin (Scheme 23). Due to theanomeric effect, the same diastereoisomer resulted from bothanomers of 23.1, although in different yields as the abstractionof the axial hydrogen atom from b-23.1 is faster than the ab-straction of the equatorial hydrogen atom from a-23.1.

The selective removal of a methoxy protecting group in the5-position in carbohydrates was designed by coupling the oxi-dative strategy and the selective 1,6-hydrogen atom migration,(Scheme 24).[58] A specific example is illustrated by the synthe-

sis of diol 24.6 in 77 % overall yield from the methoxylated b-galactoside 24.1. The oxidative step led to dioxane 24.5 a asthe main product together with a small amount of the acetox-

ymethyl derivative 24.5 b. Theseparation of the mixture wasavoided by developing an ap-propriate workup to isolate24.6.

A redox mechanism involvingCuII as the catalytic reducingagent has been proposed forthe homolytic cleavage of theN�O bond of N-sulfonyl aziri-dines.[59] The regioselective 1,6-hydrogen-atom abstraction

Scheme 21. 1,6-HAT involving alkoxy radical.

Scheme 22. Competition between 1,5- versus 1,6-HAT in a pyranose series.

Scheme 23. Anomeric allylation by means of 1,6-HAT.

Scheme 24. Selective removal of methoxy protecting group.

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from the activated benzylic position in 25.2 by an intermediatealkoxyl radical followed by the oxidative cyclization of the re-sulting CuIII–sulfonamide 25.3 onto the carbon-centered radicalwould explain the formation of aminal 25.4 (Scheme 25 A).

This reaction should be connected to the regioselective oxida-tion of unactivated C�H bonds by dioxiranes, for which a con-certed mechanism was preferred.[60] In order to reach satisfyingyields, it is mandatory to restrict the flexibility of the tether,which can be done by playing with the Thorpe–Ingold effect(R = Me, 77 % and R = H, 13 % only). It must be noted that noselectivity was registered in the transfer of secondary hydro-gen atoms from the aliphatic tether in 25.6 (Scheme 25 B). Thismethodology did not succeed in the activation of primary ortertiary C�H bonds. Due to the presence of the electron-with-drawing substituent at nitrogen the mechanism diverges com-pletely from the CuI-mediated reductive cleavage of N-alkyl ox-aziridines developed by Aub�, which proceeds via the forma-tion of an intermediate aminyl radical.[61] Remote C(sp3)�H oxi-dation involving oxygen- and nitrogen-centered radicals hasrecently been highlighted.[6]

The hypervalent iodine-based oxidative strategy was also ap-plied by Su�rez to the synthesis of spiranic azaheterocycles, al-though with less efficiency as regard to 1,6-HAT, which ismainly related to the bulk of the aminyl radical precursor.[62]

More recently, Lee has explored the DIB/I2 methodology toaccess oxazaspiroketal-containing cephalostatin 26.2 with 90 %yield from the primary amine 26.1 (Scheme 26).[63]

The CuII-catalyzed oxidation of amidines can also be tailoredto give rise to selective 1,6-HAT to the intermediate amidinylradical 27.3 (Scheme 27). Under anaerobic conditions usingstoichiometric bis(acetoxy)iodobenzene, the reaction leads to

tetrahydropyrimidine 27.5 in 65 % yield. The use of the radicalclock and the loss of chirality of functionalized tertiary carbonatom, in a rearrangement involving 1,5-HAT, were used toprobe the radical mechanism.[64]

The occurrence of 1,6-HAT to give amidyl radical 28.2 in theregioselective rearrangement of N-bromocarbamate 28.1 wasalso reported.[65] This reaction, designed as a one-pot four-steproute for the regioselective synthesis of 1,3-diols from aliphaticalcohols, is limited to the transfer of benzylic or tertiary hydro-gen atoms. As shown in Scheme 28, the chemoselective trans-fer of the former over the latter can be performed.

In most of the above examples the involvement of a delocal-ized p-system at the radical center might be responsible forthe enhanced regioselectivity in favor of 1,6-HAT.

Metallated–imido radicals can be generated from the reduc-tion of azides. An alternative concerted mechanism involvingnitrenoid intermediates can also be envisaged for these reac-tions.[66] A radical mechanism implying 1,6-HAT was proposedto rationalize the regioselective intramolecular amination ofthe sulfamoyl azide 29.1 catalyzed by a CoII–porphyrin com-plex (Scheme 29).[67] The reaction would proceed via the inter-mediate radicals 29.2 and 29.3 to give the cyclic sulfamide29.4 in high yield.

Scheme 25. Regioselectivity in CH amination of oxaziridines.

Scheme 26. Cephalostatin analogue giving an aminyl radical through 1,6-HAT.

Scheme 27. Synthesis pyrimidines through oxidative cyclization of amidines.

Scheme 28. Rearrangement of N-bromocarbamate through 1,6-HAT.

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The ring opening of the cyclopropylmethyl radical clockargues in favor of the radical mechanism. However, the highlevel of retention of configuration (30.1!30.2) might as wellbe taken as an evidence for the prevalence of a concertedpathway than as a support to the radical mechanism by con-sidering the partial racemization. A 90 % ee product was isolat-ed from a 99 % ee substrate (Scheme 30). According to DFT cal-

culations and EPR spectroscopy, the intermediate is best de-scribed as a formal CoIII “nitrene radical anion ligand” bearingthe almost entire spin density on the nitrogen atom. Zhangand co-workers have recently extended this indirect synthesisof 1,3-diamines from aliphatic amines to the amination ofpropargylic position.[68]

A dual mechanism was also discussed for the C�H bond in-tramolecular amination mediated with an iron(II)–dipyrrinatocatalyst.[69] In contrast to the above examples with a cobalt cat-alyst, the iron-catalyzed amination leads to a mixture of piperi-dine 31.2 a and pyrrolidine 31.3 a in 1:0.9 ratio. Similarly, com-peting 1,6- and 1,4-HAT were observed from 31.1 b (1:1.5 ratio)(Scheme 31). The retention of configuration of (R)-2-phenyl-5-azidopentane (through 1,5-HAT) and the preservation of the

cyclopropyl unit in the rearrangement of 2-(4-azidobutyl)cyclo-propyl)benzene both suggest that if a stepwise mechanism isoperative, the radical intermediate following hydrogen-atomabstraction is short-lived. The authors concluded that a directinsertion would be prevalent when C�H bond stronger thanbenzylic ones are functionalized.

4.1.2. Norrish–Yang rearrangement of ketones

As already stated, much attention has been paid to the synthe-sis of cyclobutanols by means of Norrish–Yang reactions, buthydrogen migration other than 1,5-migration has been suc-cessfully achieved.[34] Representative early examples of photo-cyclization to cyclopentanols in the synthesis of natural prod-ucts are given in Scheme 32. Krauss used this strategy in the

Scheme 29. 1,6-HAT in the CoII-catalyzed reduction of sulfamoyl azides.

Scheme 30. Intramolecular amination catalyzed by CoII.

Scheme 31. Regioselectivity in FeII-catalyzed intramolecular amination.

Scheme 32. Representative examples of 1,6-HAT in Norrish–Yang reactions.

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synthesis of Paulownin 32.3 (Scheme 32 A).[70] The targetedlignan was formed in 68 % yield taking into account the recov-ered substrate. Cyclopentanol 32.5 was the key intermediatein the synthesis of isotretronecanol reported by Gramain(Scheme 32 B).[71, 72]

More recently, Zhang et al. have designed isoindolones toobtain benzopyrrolizidines through the Norrish–Yang reaction(Scheme 32 C).[73] These alkaloids are still receiving attentionbecause of their wide range of biological activities, such askinase inhibition, and antitumor and antibiotic activity. The dia-stereoselective photocyclization of the ketoindolones 32.7 a af-forded the pyrrolizidinone 32.8. The rearrangement of 32.7 bled to the pyridopyrrolizidinone 32.9 in high yield. The diaste-reoselectivity varied with the nature of the activated carbonylgroup.

It should be noted that in the above-mentioned examples,no hydrogen atom was suitably located to undergo 1,5-hydro-gen migration. No competitive process could prevent the 1,6-HAT.

Yamada and co-workers have recently reported that thepresence of a tetraalkylammonium salt influenced the diaste-reoselectivity of the Norrish–Yang cyclization of phenone 33.1(Scheme 33).[74] Ab initio calculations supported that the dual

interaction of the tetraalkylammonium cation with the aromat-ic ring and the carbonyl group modifies the preferred confor-mation of the substrate so that the two aromatic ringsbecome anti in the resulting complex. This conformationalchange completely reverses the diastereoselectivity of the five-membered ring closure. The trans-isomer of dihydrobenzofura-nol 33.2 becomes the preferred product (d.r. = 93:7 at 99 %conversion) in the presence of at least three equivalents oftetra-n-butylammonium fluoride (TBAF).

Giese has described the construction of enantiopure prolinederivatives, bearing contiguous tetrasubstituted stereocenters,from optically pure alanine derived precursors. In these photo-chemically induced-1,6-HAT reactions, the transfer of chirality isbased on the memory of chirality phenomenon.[75]

The captodative radical center in biradical 34.2 is generatedin the chiral conformation shown in Scheme 34. In the pres-ence of a triplet quencher (naphthalene), the recombination ofthe singlet diradical is faster than the racemizing rotationsaround the single bonds pivots. The authors have estimated

the activation energy for the recombination of the singlet dir-adical lower by about 3 kcal mol�1 than the barrier to racemiza-tion, which implies rotations around single bonds a, b, and g.This can explain the recorded high level of memory of chirality.The recombination afforded the cis-diastereomer 34.3 a (92 %ee) with retention of configuration with respect to the stereo-center of the starting material. The minor trans-isomer also ex-hibits a high ee (88 %). Theoretical calculations have shownthat, in the preferred transition state, the compatibility ofO···H···N distances with a hydrogen bonding interaction can ex-plain the control of the diastereoselectivity. When the reactionwas conducted in the presence of a triplet sensitizer (benzo-phenone), the enantiomeric excess dropped. In other words,the triplet state lifetime is long enough for the racemization toproceed.

When the atom adjacent to the hydroxyl group bears a leav-ing group X, the C�X bond becomes weaker and its heterolysisresults in the shift of spin density by one atom (Scheme 35 A).This concept called spin-center shift (SCS) is involved in biolog-ical processes, it has also found valuable applications in syn-thesis.[76]

When this type of radical is generated from a Norrish II reac-tion, at least four different pathways can formally be observeddepending on the structure of the excited ketone. As a repre-sentative example, oxazinone 35.4 can be prepared from the

Scheme 33. Tetraalkylammonium-templated Norrish–Yang cyclization.

Scheme 34. Enantioselective Norrish–Yang reaction involving 1,6-HAT.

Scheme 35. 1,6-HAT-based photochemical synthesis of oxazinones.

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irradiation of b-ketoamide 35.1 (Scheme 35 B) by means ofa cascade combination of 1,6-HAT/fragmentation/recombina-tion.[77]

4.2. 1,6-HAT involving carbon-centered radicals

4.2.1. 1,6-HAT/1,5-HAT

Intramolecular-HAT to vinyl and aryl radicals has been exten-sively studied with the aim to understand the influence ofstructural parameters.[78–81] The ratio of the products issuedfrom competitive processes in some specific systems are high-lighted in Figure 2. They are representative of the multifactorinterplay.

These fundamental studies have led to the development ofclever tandem or more sophisticated cascade reactions initiat-ed by 1,6-HAT. Only one example of a cascade, which high-lights competitive 1,5- and 1,6-HAT will be discussed below.

4.2.2. Exclusive 1,6-HAT

Whenever regioselective 1,6-HAT can proceed, more complexreactions involving tandem ring closure can be devised. Exam-ples are given below; they appear more or less by order of in-creased complexity.

The necessarily regioselective intra-HAT from the methylenegroup, which transforms vinyl radical 36.2 into the stabilizedradical 36.3 was exploited by Reiser and co-workers to preparethe 2,3-disubstituted dihydrobenzofuran derivative 36.4 from36.1. The tandem radical translocation/conjugate addition ena-bles the transformation to proceed with an overall 81 % yield(Scheme 36).[82]

Following the same strategy, an access to the mitomycincore system was attempted by Parsons (Scheme 37).[83] It mustbe emphasized that unwanted products resulting from thecompetitive 6-endo-trig cyclization of intermediate radical 37.3were also isolated as by-products (R = H, 6 %; R = OMe, 20 %).

During the course of biomimetic studies on the fate of DNAC5’ radical,[84] Chatgiglialoglu has developed a radical cascadefrom bromodeoxyadenosine 38.1. This combination of the fast1,6-translocation and subsequent radical addition to the ade-nine moiety further proved to be synthetically useful(Scheme 38). No competitive 1,5-HAT from C4 was men-tioned.[85]

Yoshimura and co-workers transposed this strategy to pyri-midine C-cyclonucleosides.[86] These authors described the syn-thesis of C-cyclouridine derivatives by means of 1,6-HAT fol-lowed by intramolecular addition. When the 6-phenylselenouri-dine derivative 39.1 was refluxed in toluene in the presence of

Figure 2. Competitive 1,5-, 1,6- and 1,7-HAT in some specific cases.

Scheme 36. Synthesis of 2,3-disubstituted dihydrobenzofuran through 1,6-HAT.

Scheme 37. Access to mitomycin core by tandem 1,6-HAT/5-exo ring closure.

Scheme 38. Selective generation of C5’ radical from 8-bromodeoxyadenosin.

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TTMSS and AIBN, the 5’-S-epimer 39.4 was isolated as themajor product. The 5’-R-epimer was also isolated in 11 % yield(Scheme 39).

Similarly, the aryl radical 40.1, generated from the reactionof the corresponding aryl bromide with Bu3SnH, is prone toundergo selective 1,6-HAT from the ribose moiety to affordradical 40.2 (Scheme 40).[87] The occurrence of 1,6-hydrogen-atom abstraction was confirmed by deuterium labeling. Due tothe stereochemistry of the starting material, no competitiveabstraction at C2 can occur. The C�C bond formation throughintramolecular addition to the silicon-tethered vinyl groupthen takes place.

Under kinetic control at room temperature, the 5-exo-cycliza-tion mode affords radical 40.5. According to the authors,under thermodynamic control at 130 8C, the more stabilizedsix-membered ring radical 40.3 is formed from the rearrange-ment of the cycloalkylmethyl radical 40.5. Depending on ex-perimental conditions, subsequent reduction by Bu3SnH andeventually Tamao oxidation yielded diols 40.6 or 40.4 in 50 or47 % yield, respectively. The stereochemistry of the furanose

ring was inverted at C5. The complete control is due to thehindering of a-face of the furanose ring by the benzylideneprotecting group.

The combination of radical addition/1,6-HAT/radical cycliza-tion was investigated by Bachi (Scheme 41).[88] The addition of

tributylstannyl radical to the triple bond generates radical41.2, which undergoes 1,6-HAT from the captodative position.This leads to the stabilized radical 41.3, which in turn rearrang-es to 41.4 upon cyclization. The subsequent b-scission gives41.5. The conjugated isomeric product 41.6 was isolated inoverall 40 % yield after base-promoted 1,3-proton shift.

A methodology starting with a radical addition to a terminalalkyne was also utilized by Wille to promote transannular HAT.However, competitive 1,5- and 1,6-HAT were observed in sys-tems like 42.1 (Scheme 42).[89] Intermolecular addition is fol-lowed by intra-HAT, tandem ring closure and finally b-scissionto afford 42.4 a,b. At best, a 1.1:1 ratio of 1,5-/1,6-HAT resultedfrom this original “self-terminating oxidative cyclization meth-odology”.

More recently, Simpkins and co-workers have achieved an el-egant synthesis of the asperparaline core 43.5 by a similar radi-cal cascade involving 1,6-hydrogen abstraction.[90] The reactionproceeds through intermolecular addition of PhSC to 43.1, fol-lowed by regioselective 1,6-radical translocation resulting inradical 43.3. Cyclization according to the 6-exo mode leads to43.4, which undergoes 5-exo ring closure followed by reduc-

Scheme 39. Synthesis of C-cyclouridine by 1,6-HAT.

Scheme 40. Tandem selective 1,6-HAT/radical addition from ribose moiety.

Scheme 41. One-pot, four-step sequence leading to bicyclic lactams.

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tion with tributyltin hydride to afford the pentacyclic com-pound 43.5 in moderate yield (30 %), but as a single diastereo-mer (Scheme 43).

Malacria et al. have exploited two 1,6-HAT in an amazing cas-cade leading to the bicyclo[3.1.1]heptane framework of com-pound 44.8 (Scheme 44).[91] This skeleton was built through

a sequence of six elementary steps followed by the one potcleaveage of the O�Si bond. Thus, the generation a-silyl alkylradical 44.2 is followed by 5-exo-dig ring closure. The resultingvinyl radical 44.3 abstracts a propargylic hydrogen atom (1,6-HAT) to give 44.4. The subsequent diastereoselective 6-endo-trig cyclization of the resulting stabilized propargylic radicalleads to radical 44.5 as a single diastereomer. The isopropylgroup plays a determining role in the diastereocontrol of thiselementary step. When it is replaced by a less sterically de-manding group, namely an ethyl group, the diastereomericratio is lowered to 60:40. The cyclization of radical 44.5 accord-ing to the 4-exo-dig mode assembles the tricyclic intermediate44.6. This disfavored cyclization mode is driven forward bya second 1,6-HAT to the vinylic radical center in 44.6, whichgives rise to the more stabilized a-silyl radical 44.7.

The use of Bu3SnD validated the proposed mechanism. Aftertreatment by MeLi, 44.8, exclusively deuterated at the methyl-silyl group, was isolated. No deuterium-labeled vinyl groupwas detected in the product.

Penory and co-workers have investigated the rearrangementof the aryl radical issued from o-iodoanilide 45.1. Radical 45.2was generated by photoinduced electron transfer. Its rear-rangement by a cascade 1,6-radical translocation/addition tothe aromatic ring/fragmentation of the C�N bond led toamidyl radical 44.4. The latter was reduced to amide 45.5, iso-lated in 70 % yield (Scheme 45).[92] Side products were issuedfrom the nucleophilic substitution of the iodide by thioureaanion. This overall cascade resulted in 1,4-phenyl group migra-tion.

4.2.3. Pseudo-unimolecular 1,6-HAT

In connection with the diaste-reoselective method developedby Gansauer for the reductionof epoxides (see Scheme 19),[48]

it is worth citing the procedurereported by Okamoto et al.(Scheme 46).[93] A low-valent tita-nium species, generated in situfrom [Ti(O-iPr)4] , Me3SiCl, andMg powder in THF, is responsi-ble for the regioselective reduc-tive cleavage of the C�O bond.The intermediate carbon-cen-tered radical is reduced through1,6-hydrogen-atom migrationfrom the [Ti(O-iPr)4] to afford46.4. The preference for the lesshindered cis-fused seven-mem-bered transition state controlsthe diastereoselectivity of thereaction.

The mechanistic proposal wasconfirmed by performing the re-duction in [D8]THF followed by

Scheme 42. Transannular cascade involving competitive 1,5- and 1,6-HAT.

Scheme 43. Synthesis of asperparaline core via 1,6-HAT.

Scheme 44. Synthesis of bicycle[3,1,1]heptanes by a double 1,6-HAT.

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the quenching of the reaction with D2O. The resulting alcoholshowed no incorporation of deuterium. This result discardedintermolecular hydrogen-atom transfer from the solvent. Addi-tional assessment was given by using deuterium-labeled titani-um isopropoxide.

4.2.4. 1,6-HAT in rearrangements involving biradicals

Since the discovery of their anticancer activitities, the reactivityof enediynes and enyne–allenes has attracted continuous inter-est.[94] In 2009, Schmittel has reported a novel photochemicallyinduced enyne–allene cyclization.[95] Based on DFT calculationsand laser flash photolysis experiments, the authors proposedthe mechanism detailed in Scheme 47. In this reaction, the re-arrangement of the excited triplet state of the allene moietyleads to biradical 47.2 through C2–C6 cyclization.[96] Subse-

quent fast cyclopropyl ring opening affords diradical 47.3,which undergoes internal disproportionation by 1,6-migrationof a hydrogen atom from the methylene group, to afford theconjugated diene 47.4 (Scheme 47).

More recently, Bertrand, Nechab, and co-workers have inves-tigated enantioselective rearrangements of enyne–allenes pro-ceeding with memory of chirality.[97] They have demonstratedthrough deuterium labeling experiments that exclusive 1,5- or1,6-hydrogen transfer was involved in the reaction dependingon the nature of the substrate.[98]

As exemplified in Scheme 48, enyne–allene 48.2 was gener-ated in situ by a base-induced 1,3-proton shift. GA-SBA-15,a mesoporous silica grafted with a tethered tertiary amine, wasused to this purpose. Saito–Myers cycloaromatization led tothe s,p-biradical 48.3. This radical was designed to undergosubsequent 1,5-hydrogen-atom transfer from the captodativeposition and eventually recombination to afford 48.5 ab.[97a]

The potentially competitive 1,6-hydrogen-atom migrationbecame the exclusive pathway in the case of the valine deriva-tive (R = iPr). The alkene 48.7 was isolated as the unique prod-uct in 64 % yield. It resulted from internal disproportionation ofbiradical 48.6 (via 1,8-HAT). The formation of 48.7 with no al-teration of the enantiomeric excess was an additional proof toexclude any abstraction of the hydrogen atom at the stereo-

Scheme 45. 1,6-HAT-promoted 1,4-migration of aryl group.

Scheme 46. 1,6-HAT in low-valent Ti-induced reduction of epoxides.

Scheme 47. Sequential Schmittel cyclization/cyclopropane ring opening/in-ternal disproportionation by a 1,6-HAT in the rearrangement of enyne–al-lenes.

Scheme 48. 1,5-/1,6-HAT reaction in the rearrangement of enyne–allenes.

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center. DFT calculations have shown that when R = iPr, the twocompetitive HAT reactions have similar exergonicities.

The ability of the system to reach the conformations of dir-adical 48.3 that are best suited to 1,5- or 1,6-HAT is dependenton the conformational strain arising from the bulk of the sub-stituent at nitrogen. Rates constants for the rearrangement ofrelated aryl radicals linked to an amino acid moiety have beendetermined by Schiesser.[14] These results led to the design ofpotential precursors of enantiopure naphthoazepines 49.2.[99]

In this case, the formation of the intermediate enyne-allene49.4 resulted from Crabb� homologation. However, the target-ed product was isolated in only 38 % yield. The side product49.3 issued from internal disproportionation of diradical 49.5(via 1,8-HAT) accounted for 24 % yield (Scheme 49).

1,6-HAT was reported in closely related systems in which nocompetitive 1,5-HAT could be observed.[100] In this reaction, theallene moiety was replaced by an in situ generated vinylidene–rhodium complex. Saito–Myers-like cyclization was followed byunequivocal 1,6-HAT (or 1,7-HAT depending on the structure ofthe starting enediyne, see Scheme 56). Recombination was im-mediately followed by reductive elimination of RhI

(Scheme 50).

5. 1,7-Hydrogen-atom transfer

As evidenced in the previous section, many reports deal with1,6-hydrogen-atom transfers; however, their 1,7-HAT counter-parts are comparatively scarce. Based on the number of re-corded occurrences in the literature, they are as difficult toachieve as 1,8-HAT. Only enthalpically favored 1,7-HAT, whichdid not suffer from competitive 1,5- or 1,6-HAT, proved to havesome synthetic value.

While exploring the potential of oxidative cyclizations,Su�rez has proven that 1,7-HAT was the major evolution of thebenzyl b-d-ribofuranoside-derived alkoxy radical 51.1. In thisspecific situation, the exothermicity of 1,7-HAT was coupledwith the stereochemical impediment of 1,5-HAT from the

anomeric position (Scheme 51).[101] The benzylic radical adja-cent to oxygen resulting from an eight-membered cyclic transi-tion state led to acetal 51.2 in 42 % yield through oxidativecyclization. In this case, the competing reaction was the b-frag-

Scheme 49. Naphtoazepines from the cascade rearrangement of enyne–al-lenes involving 1,6-HAT.

Scheme 50. 1,6-HAT in the cycloaromatization of vinylidene–Rh complexes.

Scheme 51. Enthalpically and stereochemically favored 1,7-HAT in benzyl b-d-ribofuranoside.

Scheme 52. Tin-free regioselective O-debenzylation of pyranosides through1,7-HAT.

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mentation of the alkoxyl radical 51.1, which led to acetate51.3 in 28 % isolated yield after oxidation (Scheme 51).

Beau and co-workers have devised a tin-free strategy for theregioselective O-debenzylation of a vicinal position in a- andb-d-pyranosides series. This method is based on the favorableenthalpy of intra-HAT from the methylene of the protectingbenzyloxy group.[102] As shown in Scheme 52, xanthate 52.1grafted on a temporary silylated tether was submitted to theexperimental conditions previously developed by Zard (di-chloroethane at reflux, in the presence of 2 equivalents of di-lauroyl peroxide (DLP)).

The intermediate radical 52.2 evolves to radical 52.3through 1,7-HAT. Subsequent oxidation of the latter by DLPgenerates the benzylic cation 52.4, which is trapped by the re-leased carboxylate. Acidic workup and TMS removal by TBAFprovided diol 52.6 in 85 % isolated yield. It is worth notingthat 1,7-HAT is favored over 1,4-HAT from C2 and even over1,5-HAT from C1 or C3. Radical 52.3 is formed selectively. Thiswas clearly demonstrated by the regioselective deuterium la-beling of the reactive benzyloxy group under reductive condi-tions. The methodology was successfully extended to disac-charide derivatives.

The selection of appropriate carbonyl compounds enablesNorrish type II reaction to generate 1,7-biradicals.[34c] Asparticderivatives 53.1 a–c were engaged in highly diastereoselective1,6-photocyclizations affording 53.3 a,b or 53.4 c in goodyields. NOE experiments were used to establish the stereo-chemistry of the products. The preference for a chair-like tran-sition state, in which the phenyl group is equatorial in order tominimize 1,3-diaxial repulsive interactions, was suggested toexplain the diastereoselectivity in the 1,6-diradical recombina-tion step (Scheme 53).[103] The formation of stabilized benzylicor captodative radicals intermediates is the driving force forthe observed 1,7-HAT. Surprisingly, competitive hydrogen ab-straction from the methyl group was observed with the N-methyl derivative 53.1 c. The impact of the steric bulk of thenitrogen substituent on the regioselectivity of intra-HAT has al-ready been mentioned in this Review (see: Scheme 48, [97]).

Other stereoselective photocyclizations leading to d-lactamsfrom 4-oxo-4-phenyl butanoyl amines according to this strat-

egy had previously been reported by Wessig.[104a] This authorhas further extended the methodology to the synthesis of bi-cyclic b-turn dipeptides from (S)-proline (Scheme 54).[104b] Simi-

lar yields were obtained with other amine protecting groupslike carboxybenzyl (Cbz) and allyloxycarbonyl (Alloc). Converse-ly, the presence of the fluorenylmethyloxycarbonyl (Fmoc) pro-tecting group, which contains a biphenyl moiety, led to thequenching of the benzoyl group triplet excited state and pre-vented the reaction. It is worth noting that the preferential 1,7-HAT from the (S)-proline moiety of 54.1 did not occur from thecaptodative position. The opposite behavior, in better agree-ment with enthalpic effects, would have been expected.[99, 105]

Van Dort and Fuchs have designed a radical self-immolative1,2-elimination to promote the desulfonation of aryl sul-fones.[106] Thus, the a-silyl radical 55.2, generated from theauto-sacrificial aryl sulfone moiety of 55.1, evolved through1,7-HAT via an eight-membered cyclic transition state. This ab-straction of a hydrogen atom in the b-position with respect tothe sulfone, promoted b-fragmentation to afford the alkene55.4 together with the sulfinate 55.5. No 6-exo-dig cyclizationcompeted with the fast b-scission (Scheme 55).

As already mentioned, Uemura and co-workers have exploit-ed the cycloaromatization of a vinylidene–Rh complex to trig-ger the formation of silacycloalkanes fused to aromatic rings(for 1,6-HAT, see: Scheme 50).[100] The stabilizing effect of a-sili-

Scheme 53. 1,7-HAT in Norrish type II photocyclizations.

Scheme 54. 1,6-Photocyclization leading to bicyclic b-turn dipeptides from(S)-proline.

Scheme 55. Desulfonation of aryl sulfones by 1,7-HAT.

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con atom was assumed to compensate the unfavorable entro-py of the formation of the eight-membered cyclic transitionstate involved in the Rh-catalyzed rearrangement of 56.1.Compound 56.3 was isolated in 55 % yield from reductive elim-ination of the intermediate rhodacycle 56.2 (21 % of the sub-strate was recovered unchanged) (Scheme 56).

6. 1,n-Hydrogen-atom transfer (n>7)

6.1. 1,8-HAT

Most examples in this series involve oxygen-centered radicals.Su�rez has expended the remarkable potential of intra-HATpromoted by alkoxyl radicals to the construction of polycyclicoxygen-containing ring systems.[107] In order to perform remotefunctionalization of synthetic value, via nine- or even higher-membered cyclic transition states, a restricted conformationalflexibility must be introduced to overcome the entropic penal-ty. These authors have investigated intra-HAT between twopyranose units. In such systems the enthalpically favored mi-gration of a hydrogen atom a to oxygen can be coupled withadjustable conformational restriction.

According to crystallographic data and molecular mechanicscalculations, methyl b-d-maltoside 57.1 was a good candidate.This compound was submitted to oxidative cyclization in thepresence of DIB and iodine (Scheme 57).[108] The correspondinghypoiodide formed in situ was the precursor of the alkoxy radi-cal at C6; it led to the C5’-fuctionalized disaccharide 57.2 in62 % yield. The C5’ hydrogen-atom abstraction was favoredover 1,6-HAT from C1’. This was confirmed by studying the re-activity of the N-hydroxyphthalimide 58.1 under reductive con-ditions, that is, in the presence of Bu3SnD/AIBN, which afforded58.2 and its C5’ epimer with complete incorporation of deute-rium at C5’ (Scheme 58).

A comparative study performed on the analogous C-disac-charide pointed to the greater flexibility of the C-glycosidicbond and the lack of anomeric effect. No selectivity in intra-HAT was observed, as shown in Figure 3.[109]

Selective C5’ functionalization was also recorded from nitro-gen-centered sulfonamidyl radicals although in slightly loweryields.[110]

The photochemically induced 1,8-abstraction of a hydrogenatom from 59.1, performed from the triplet excited state ofthe benzophenone moiety, was proposed to explain the forma-tion of 59.2. The spirocyclic intermediate 59.3 would resultfrom the vinylogous recombination of diradical 59.2. Apparent-ly, this biradical coupling is faster than the b-scission releasinga bromine atom. Rearomatization by ring opening would befollowed by intramolecular nucleophilic ring closure. The tricy-clic-bridged lactam 59.5 was isolated in 56 % yield(Scheme 59).[111, 112]

Scheme 56. Formation of eight-membered rhodacycle by 1,7-HAT.

Scheme 57. 1,8-HAT in O-disaccharides.

Scheme 58. Mechanistic proof for 1,8-HAT by deuterium-labeling.

Figure 3. Lack of selectivity in intra-HAT from C-disaccharide.

Scheme 59. 1,8-HAT from excited benzophenones.

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An unprecedented highly stereoselective internal dispropor-tionation of biradical 60.2 a was shown to occur as side reac-tion in the photocyclization of N-(w-hydroxyalkyl)-tetrachlor-ophthalimide 60.1 a with 1-phenylcyclohexene, after intersys-tem crossing (ISC) to the singlet excited state (Scheme 60).[113]

In this reaction, the photoinduced electron transfer from thetriplet excited state of the phthalimide to the alkene is fol-lowed by intermolecular coupling of the triplet ion–radical pairto give biradical 60.2 a.

Whereas the expected ISC followed by recombination ex-plains the formation of 60.3 a in 33 % yield, a fully stereocon-trolled 1,8-HAT explains the formation of the acyclic product60.4 a in 21 % yield. With the homologuous phthalimide 60.1 bleading to the eight-membered-ring tetracyclic heterocycle60.3 b, the disproportionation product 60.4 b, formed from ste-reoselective 1,9-migration of the hydroxyl hydrogen atom,became the major product (36 %).

6.2. Long-distance 1,n-HAT (n�9)

To circumvent the entropic penalty in the macrocyclization,Kraus and Wu have designed a rigid molecular scaffold, whichfavors 1,9-HAT by preventing any passage by a shorter mem-bered transition state.[114] The syn-rotamer of the ester group in61.1 is likely to be responsible for the observed selectivity. Theprocedure led to the eight-membered ring lactone 61.3(Scheme 61 A). Deuterium labeling experiments have excludedthe possible interference of two subsequent 1,5-HAT steps asthe deuteromethylene group was not affected in the finalproduct 61.3. Similarly, owing to the rigidity of its ester moiety,61.4 led to lactone 61.5 in 74 % yield (Scheme 61 B).

As far as long-range intra-HAT are concerned, a tribute mustbe paid to the seminal work of Breslow, who was the first to

imagine how rigid skeletons might open routes to selectiveremote functionalization.[115, 116]

The design of appropriate linkers to anchor the benzophe-none moiety to the steroid skeleton led to elegant selectivefunctionalizations. As shown in Scheme 62 A, the irradiation ofthe benzophenone-4-acetic ester of 3-a-cholestanol (62.1 a)led to selective HAT from position 14. Alkene 62.3 a, which re-sulted from the subsequent internal disproportionation of dir-adical 62.2 a, was isolated in 55 % yield.[115a] This elegant reac-tion was further applied to prepare the pavinonin-4 aglycone62.2 b (Scheme 62 B) via the corresponding alkene intermedi-ate,[117 ]and the tetracyclic alkene 62.2 c (Scheme 62 C).[118]

Intramolecular regioselective remote chlorination was per-formed in high yield by devising an iodophenyl template totemporarily complex the chlorine atom 62.2 d (Sche-me 62 D).[115b]

Miranda has long been interested in this topic to designsubstrates capable to give chiral discrimination in the hydro-gen abstraction step.[119] He has investigated the fate of diaste-reomeric dyiads made from convalently linked ketoprofen ((R)-or (S)-Kp) and a-cholesterol units (Scheme 63).

Selective allylic C�H abstraction from C7 was promoted byirradiation. It is worth noting that only one product resultedfrom the tandem intra-HAT/recombination process when start-ing from (R,R)-63.1 b, whereas two diastereomers were isolatedfrom (R,S)-63.1 a.

A remarkable regio- and stereo-differentiation was found inthese systems. Flash photolysis of Kp derivatives enables long-range HAT to be performed. The recombination step enablesthe diatereotopic faces of the newly created carbon-centeredradical to be discriminated (Scheme 64). Other types of linkerwere investigated.[120]

As illustrated in Scheme 65, the authors have measured bylaser flash photolysis the rate constant at room temperature ofintra-HAT for both diastereomers of the Kp–tetrahydrofurfuryla-mine dyad. A completely regioselective HAT was observed. Nocompetitive abstraction at C2 leading to the tertiary a-THF rad-ical was detected. DFT calculations confirmed that the activa-tion energy for intra-HAT at C5 is 8.8 kcal. mol�1 lower thanthat for abstraction at C2.

The unimolecular rate constant kH for this elementary step isequal to 3.0 � 105 s�1 for the (S,S)-tetrahydrofurfurylamide 65.1.It is four times higher than the rate constant measured for the

Scheme 60. Stereoselective internal disproportionation through 1,8- and 1,9-HAT.

Scheme 61. Macrocyclization through 1,9-HAT.

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(R,S)-diastereomer.[120c] The photoinduced reaction affordedonly two diastereomers out of the four possible ones in a 1:1ratio in the first case. Conversely, when the (R,S)-Kp–THF dyadwas irradiated, four photoproducts were obtained from the re-action. The diastereodifferentiation is clearly connected to the

triplet lifetime of the carbonyl chromophore, which decayedmuch faster in the case of the (R,S)-diastereomer.[121]

In the continuation of their early work, the same group hasalso reported the photolysis of some other dyads of biologicalinterest.[122]

The decay of acetophenone triplets is greatly facilitated byhydrogen bonding with a phenol proton. The net long-rangehydrogen-atom transfer leading to phenoxyl radical and hemi-pinacol radical was shown to be strongly sensitive to polar ef-fects. According to Hammet’s plots, the ketone triplet exhibitsa nucleophilic character in this reaction. Intramolecular systemsin which the aromatic ketone is linked to the phenol moietyby spacer groups of varying chain lengths have been investi-gated.

Scheme 62. Breslow’s remote functionalization methodology.

Scheme 63. Diastereoselectivity in tandem regioselective long-range HAT/re-combination process.

Scheme 64. Principle of chiral recognition in the laser flash photolysis of ke-toprofen derivatives.

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The triplet lifetime is controlled by the rate of intramoleculartransfer of the phenolic hydrogen atom. The fast triplet decaywas related to the formation of sandwich (or cyclophane-like)conformers in which hydrogen bonding is reinforced. Thesestructures would favor the decay via the formation of a hydro-gen-bonded triplet exciplex followed by electron transfer cou-pled to proton transfer. A system in which net 1,n-HAT (wheren>10) is involved is illustrated in Scheme 66.[123]

The investigation of templating effects and chiral recogni-tion in photoactivated reactions, which might have importantbiological repercussion, has stimulated many research groups.A stepwise electron-transfer/proton-transfer mechanism waslikewise suggested for the net long-range HAT between tyro-sine and triplet-excited benzophenone in protic solvent.[124]

The rate constants for these processes were found strongly de-pendent on the solvent with k ranging from 105 to 5 � 107 s�1.The rate decreased with the hydrogen-bond accepting proper-ties in aprotic solvents. Conversely, a sharp increase of the re-action rate with the hydrogen-bond donor ability of the sol-vent was observed in protic solvents.

A similar mechanism, involving intramolecular electron trans-fer from the methylsulfide moiety of the methionine unit ofdyad 67.1 towards the excited benzophenone unit, was pro-posed to explain the formation of 67.5 (Scheme 67).[125] These

biomimetic studies of a ring closure through C�C bond forma-tion, resulting from net regioselective long-range intra-HAT,might open new applications in asymmetric synthesis of mac-rocycles. The question of chirality transfer in these reactionsshould be addressed.[126]

Hydrogen-atom transfers are involved in many biologicalprocesses. The fundamental knowledge of these reactions is ofprime importance to understand the mechanisms of DNAcleavage and peptides and proteins modifications through ra-diation damage.[127, 128] Intra-HAT reactions have been investi-gated both from theoretical[9] and experimental point ofviews.[129] It is worth mentioning that thiyl radicals, which arenot widespread as hydrogen-atom abstractors compared tooxygen-centered radicals,[130] and more particularly sulfanyl rad-icals formed from cysteine residues are particularly active inlong-range HAT in proteins and peptides.

As an illustrative example of peptide modification, Renaultand co-workers demonstrated that a long-distance intramolec-ular hydrogen-atom transfer to carbon-centered radicals couldalso occur in peptides (Scheme 68). Deuterium labeling ena-bled these authors to prove the involvement of intramolecular

Scheme 65. Reactivity of (S,S)-Kp–tetrahydrofurfurylamine dyad.

Scheme 66. Decay of acetophenone triplet excited state favored by internalhydrogen-bonding to phenol (net 1,n-HAT where n�10).

Scheme 67. Photoinduced C�C coupling as a result of net long-range HATin methionine dyads.

Scheme 68. Long-range intra-HAT between amino acids side chains.

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hydrogen-atom exchange between two leucine residues bygenerating the radical at a leucine side chain upon g-radiolysisin water.[131]

7. Summary and Outlook

The relevance of 1,n-HAT to naturally occurring biological pro-cesses confers a prime importance to biomimetic mechanisticstudies. Besides this fundamental interest, the investigation ofthe less commonly encountered 1,n-HAT reactions in whichn¼6 5 has led to high yielding original synthetic applications.Most of these processes that offer selective routes to C�H acti-vation are diastereo- and enantiocontrolled. The aim of thisreview was to make a critical updated inventory, highlightingthe most elegant cascade reactions based on 1,n-HAT elemen-tary step in which n = 4, 6, 7, 8, 9, and so forth. The search forasymmetric strategies involving such intra-HAT steps in sophis-ticated cascades is still a challenging field. The search of enan-tioselective remote functionalization through suitably immobi-lized radical abstractors will probably stimulate further prog-ress.

Acknowledgements

Aix-Marseille Universit� and CNRS are acknowledged for finan-cial support. DST Government of India is also acknowledgedfor financial support to S.M. through an Inspire Faculty Award.

Keywords: abstraction · C�H activation · domino reactions ·hydrogen-atom transfer · radicals

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Review