Thiyl radicals in organic synthesis.

Review pubs.acs.org/CR

Thiyl Radicals in Organic Synthesis Fabrice Dénès,*,† Mark Pichowicz,‡ Guillaume Povie,‡ and Philippe Renaud‡ †

Laboratoire CEISAM UMR CNRS 6230 - UFR des Sciences et Techniques, Université de Nantes, 2 rue de la Houssinière, BP 92208 - 44322 Nantes Cedex 3, France ‡ Department of Chemistry and Biochemistry, University of Berne, Freiestrasse 3, CH-3012 Bern, Switzerland 3.1. Addition of Thiols to Simple Alkenes (Interand Intramolecular Addition) 3.1.1. Intermolecular Addition: The “Thiol−Ene Coupling” Reaction 3.1.2. Intramolecular Addition 3.2. Addition onto 1,3-Dienes 3.3. Cascade Reactions 3.3.1. Intermolecular Trapping of the CarbonCentered Radical 3.3.2. Intramolecular Trapping of the CarbonCentered Radical 3.4. Addition of Thiyl Radicals to Allenes 3.4.1. Intermolecular Addition to Allenes: Regioselectivity 3.4.2. Intermolecular Trapping: Dichalcogenation 3.5. Miscellaneous 4. Addition of Thiols to Alkynes and Related Carbon−Carbon Triple Bonds 4.1. Simple Addition to Alkynes 4.1.1. General Trends 4.1.2. Synthetic Applications 4.2. Bis-Addition of Thiols to Alkynes: The “Thiol−Yne” Reaction 4.3. Simple Addition to Electron-Rich Ynoates and Ynamides 4.4. Trapping of the Vinyl Radical Intermediate 4.4.1. Intermolecular Trapping 4.4.2. Intramolecular Trapping 5. Fragmentations of β-Sulfanyl Radicals 5.1. Reversibility of the Addition Process: Isomerization of Alkenes 5.2. Allylation, Allenylation, and Vinylation Reactions with Sulfides: The Fragmentation Method 5.2.1. Fragmentation of Allyl Sulfides 5.2.2. Fragmentation of Propargyl Sulfides 5.2.3. Fragmentation of Vinyl Sulfides 5.2.4. Miscellaneous 5.2.5. Other Types of Fragmentation: Desulfurization Reactions 6. Addition of Thiols to Isonitriles 6.1. General Trends 6.2. Intermolecular Trapping 6.2.1. Simple Addition versus Addition−Fragmentation 6.2.2. Double Chalcogenation Reactions

CONTENTS 1. Introduction 2. Kinetic and Thermodynamic Aspects of Reactions Involving Thiyl Radicals 2.1. Generalities 2.1.1. S−H Bond Dissociation Energies in Thiols 2.1.2. The S−S Bond Dissociation Energies in Disulfides 2.1.3. Generation of Thiyl Radicals 2.1.4. Detection of Thiyl Radicals 2.1.5. Termination Reactions 2.2. Hydrogen Atom Transfer 2.2.1. Isotope Effect 2.2.2. Carbon-Centered Radicals in Apolar Media 2.2.3. Solvent Effects and Hydrogen Atom Transfer in Aqueous Solutions 2.2.4. Silyl Radicals 2.2.5. Oxygen- and Nitrogen-Centered Radicals 2.3. Addition−Fragmentation Reactions 2.3.1. Influence of the Alkene Structure 2.3.2. Enthalpy of Reaction versus Polar Effects 2.3.3. Solvent Effects 2.3.4. Alkynes 2.3.5. Conjugated Dienes and Allenes 2.3.6. Aromatic Systems 2.4. Reactions of Thiyl Radicals at Heteroatomic Centers 2.4.1. Oxygen 2.4.2. Disulfides 2.4.3. Thiocarbonyl Compounds 2.4.4. Phosphites 2.4.5. Organoboranes 2.4.6. Miscellaneous 3. Addition of Thiols to CC Bonds

© XXXX American Chemical Society

B B B B C C C C C D D E F F F F G H H I I I I I I I J J J

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BC BD BL BM BP BR BS BS BS BS BU

Received: August 13, 2013

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dx.doi.org/10.1021/cr400441m | Chem. Rev. XXXX, XXX, XXX−XXX

Chemical Reviews 6.3. Intramolecular Trapping 6.3.1. Cyclization onto Alkenes and Alkynes 6.3.2. Cyclization to Nitriles 7. Addition onto the CS Bond of N-Hydroxypyridine-2-thiones 7.1. Generation of Carbon-Centered Radicals 7.1.1. Reductive Decarboxylation 7.1.2. Intramolecular Trapping 7.1.3. Intermolecular Trapping 7.2. Generation of Nitrogen-Centered Radicals 7.3. Generation of Oxygen-Centered Radicals 8. Thiyl-Mediated Hydrogen Atom Abstraction 8.1. Generation of Carbon-Centered Radicals 8.1.1. Hydrogen Atom Abstraction from CH− OR Positions 8.1.2. Hydrogen Atom Abstraction from CH− NR2 Bonds 8.1.3. Hydrogen Abstraction from Benzylic and Allylic Positions 8.1.4. Generation of Acyl Radicals 8.2. Generation of Silyl Radicals 8.2.1. General Trends 8.2.2. Hydrosilylation Reactions 8.2.3. Generalities on Reduction Reactions 8.2.4. Dehalogenation Reactions 8.2.5. Barton McCombie Deoxygenation Reactions 8.2.6. Reductive Alkylations 8.2.7. Reduction of Alkyl and Aryl Azides 8.2.8. Desulfurization Reactions 8.3. Hydrogen Abstraction from B−H Bonds (NHC·BH3) 8.4. Hydrogen Atom Transfer from Metal Hydrides 8.5. Hydrogen Atom Abstraction in Biological Systems 8.5.1. Ribonucleotide Reductases 8.5.2. Other Enzymatic Processes 8.5.3. Oxidative Damage to DNA 8.5.4. Hydrogen Atom Abstraction from Amino Acid Derivatives 8.5.5. Hydrogen Atom Abstraction from Unsaturated Fatty Acids 8.5.6. Hydrogen Atom/Electron Transfer from Other Antioxidants 9. Conclusion Author Information Corresponding Author Notes Biographies References

Review

ingly, these radicals have also attracted the interest of synthetic chemists, and they are at the center of some extremely efficient radical reactions. Thiyl radicals are known to add efficiently to a wide range of unsaturated systems such as alkenes, alkynes, isonitriles, and thiocarbonyl groups. The reversibility of most of these processes renders them particularly versatile, and the reverse reaction, the ß-fragmentation of 2-sulfanylalkyl radicals, is an important chain propagation step in many transformations. The remarkable reactivity of thiyl radicals makes them unique for the design of sophisticated reactions free of metal catalysis as illustrated by reactions involving highly selective hydrogen atom abstraction. The chemistry of thiyl radicals has been reviewed more than 40 years ago,3 and in the 1990s.4 More recently, some specific aspects of this chemistry such as the thiol−ene coupling reaction,5 the thiol−yne reaction,5e,6 and radical cyclizations7 have been compiled. This Review has the aim of covering in an extended manner the uses of thiyl radicals in organic synthesis and to provide sound mechanistic information to understand these processes and to design new synthetic applications.

BU BV BX BX BY BY BZ CA CB CC CD CD CD CF CH CI CK CK CK CL CL

2. KINETIC AND THERMODYNAMIC ASPECTS OF REACTIONS INVOLVING THIYL RADICALS As a good knowledge of the character of a reactive species is crucial to plan synthetic reactions, kinetic studies on small organic radicals have always preceded the development of synthetic methodologies. The following section endeavors to describe the main elementary reactions involving thiyl radicals and to discuss the factors directing the rates and selectivity of these processes.8 Being beyond the scope of this Review, the gas-phase chemistry of thiyl radicals will not be discussed, and only liquid-phase studies have been considered.9 Although this Review mainly focuses on synthetic reactions, the data presented here may be relevant to the role of thiyl radicals in biological systems.

CM CM CN CO CO CO CP CP CP CQ

2.1. Generalities

2.1.1. S−H Bond Dissociation Energies in Thiols. Alkanethiols behave almost all similarly toward hydrogen atom abstraction due to their equal S−H bond dissociation energies, generally accepted to be around 87 kcal mol−1 regardless of the structure of the alkyl residue.10,11 The S−H bond in cysteine is slightly weaker (86 kcal mol−1),10 while hydrogen sulfide is significantly less reactive (91 kcal mol−1).12 The S−H bond in thioacids is found to be in the same range (from 87 kcal mol−1 for thiobenzoic acid to 88 kcal mol−1 for thioacetic acid),12 and they generally display homolytic reactivity analogous to that of alkanethiols. Thiophenols are excellent hydrogen atom donors due to the stabilization by resonance of the corresponding arenethiyl radical. Thiophenol itself has a S−H BDE around 79 kcal mol−1, but the presence of substituents on the ring may drastically influence this value.13 As for the X−H bond in phenols (X = O) and anilines (X = N),14 electron-donating para-substituents decrease the S−H BDE, whereas electronwithdrawing ones increase it.15 Computational studies have shown that the difference of BDE mainly arises from (de)stabilization of the arenethiyl radical, the effect of substitution on the energy of the parent molecule being only minor.16 Thus, the S−H bond of 4-aminothiophenol is particularly weak (70 kcal mol−1)15a as compared to that of pentafluorothiophenol (calculated at 84 kcal mol−1)17 and paranitrothiophenol (82 kcal mol−1). Some substituents such as

CQ CQ CR CR CR CR CR CR CS

1. INTRODUCTION Thiyl radicals have been used by nature in a broad range of biochemical processes. For instance, thiol residues play an important role in many enzymatic processes as illustrated by the essential deoxygenation of ribonucleotides,1 a transformation shared by all living organisms in the de novo synthesis of DNA precursors.2 The ubiquitous character of these radicals in biological systems results from a combination of factors, including for instance their ease of formation from diverse sources and their exceptional reactivity. Not surprisB


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respectively prepared by the reaction of nitrosyl chloride or a diazonium salt with a thiol.3a 2.1.4. Detection of Thiyl Radicals. The detection of thiyl radicals has been reviewed elsewhere, and the reader is directed to these works for additional references.4d,28 Although spectra can be obtained in the solid state,29 alkylthiyl radicals are generally EPR silent in solution due to very short spin−spin relaxation times (T2) that considerably broaden the signal and decrease the signal-to-noise ratio, often below the limit of detection. As for alkoxyl radicals, this effect arises from spin− orbit coupling between degenerated orbitals in the ground state of the radical.30 The formation of a thiyl radical by addition of a muon to a thiocarbonyl group allowed their observation by EPR spectroscopy as the resulting change in symmetry lifts the degeneracy of the singly occupied orbital.31 Nitrones32 and nitroso33 spin-traps have been used to detect thiyl radicals as their nitroxyl radical adducts. Nevertheless, the limited stability of the radical adducts allows the detection only during in situ generation of the thiyl radicals, the nitroxyl radical rapidly decaying once initiation is stopped (see section 2.4.6). Thiyl radicals may be observed by UV spectroscopy, and laser flash photolysis has been an important tool to understand their reactivity.27 Because of their higher UV−vis absorption band (around 500 nm), arenethiyl radicals are easier to detect than alkylthiyl radicals; however, the latter display a weak absorption band around 330 nm.34 2.1.5. Termination Reactions. Alkylthiyl radicals recombine rapidly (2kt = (1−3) × 109 M−1 s−1),34,35 and no mention of disproportionation reactions can be found in the literature. Similarly, unhindered arenethiyl radicals have been considered to dimerize at diffusion-controlled rates.36

halogen atoms or the trifluoromethyl group have only a minor effect on the strength of the S−H bond,18 although large variations in pKa and redox potentials are observed.15a Hydropersulfides (RSSH) can be mentioned as having very weak S−H bonds (around 65 kcal mol−1),12 but they have barely been used in synthetic processes. 2.1.2. The S−S Bond Dissociation Energies in Disulfides. Sulfur−sulfur bonds in disulfides are stronger than the isostructural O−O, Se−Se, or Te−Te bonds.4d Nevertheless, the S−S may be easily cleaved, making disulfides efficient thiyl radical precursors especially useful when a nonreductive environment is required. The stability of the resulting radical governs the S−S BDE, which is found to be around 65 kcal mol−1 in dialkyldisulfides and 50 kcal mol−1 in diaryldisulfides.12 2.1.3. Generation of Thiyl Radicals. The reaction of sulfur-containing molecules with another radical is a preeminent source of thiyl radicals. Thiols can rapidly transfer a hydrogen atom to most types of radical X• having a corresponding higher X−H BDE. Therefore, all of the commonly used initiators such as azo-compounds or peroxides that generate alkyl or alkoxyl radicals are efficient to initiate thiol-mediated radical transformations. As good sources of alkyl radicals, organoboranes in combination with oxygen may be used to initiate chain processes at low temperatures.19 Thiyl radicals may be generated from a thiol and a one-electron oxidant such as Mn(III) compounds.20 Similarly, electron transfer from thiolate anions results in the formation of thiyl radicals, which has been proposed to occur with oxygen in the autoxidation of thiolate solutions.21 As the autoxidation of thiols proceeds through the formation of thiyl radicals, residual oxygen in solutions may be responsible for the initiation of some particularly efficient radical chain processes that take place in the absence of radical initiator. On the other hand, homolytic substitutions at a sulfur atom of disulfides generate thiyl radicals. The reaction is more efficient on diaryldisulfides than on dialkyldisulfides (respectively, 2 × 105 and 6 × 104 M−1 s−1 for a primary alkyl radical at 298 K).22 This process can also be promoted by tin-centered radicals, among others. Electron transfer to disulfides produces a disulfide radical anion that fragments into a thiyl radical and a thiol upon protonation.23 Homolytic cleavage of S−H or S−S bonds can be induced by radiolysis or under light irradiation. Thiols absorbed at low wavelengths (maximum of absorbance around 200 nm and a broad band centered at 235 nm for methanethiol), and different dissociation mechanisms may be involved.24 Irradiation above 300 nm is thus rather inefficient in generating substantial amounts of thiyl radicals. Nevertheless, in preparative chain reactions where only initiation is required, continuous irradiation using a sun lamp can be used even through Pyrex glass (cutoff around 280 nm). In such cases, the slow but constant initiation is an advantage because the steady-state concentration of radicals remains low, diminishing the importance of termination reactions.25 Ketones are commonly used as sensitizers under light irradiation because the triplet state of carbonyl compounds rapidly abstracts a hydrogen atom from thiols.26 Because the S−S bonds in disulfides are much weaker than any S−H bonds, they are easier to cleave photochemically, and irradiation of diphenyldisulfide at 355 nm has been used in flash photolysis experiments.27 Thiyl radicals may be generated in the thermal decomposition of thionitrites (RS−NO) or diazothioethers (RNNSR′),

2.2. Hydrogen Atom Transfer

Alkyl thiols, despite the high BDE of the S−H bond (87 kcal mol−1),10 transfer hydrogen atoms to primary alkyl radicals (k298K = 2 × 107 M−1 s−1) more rapidly than well-established hydrogen atom donors such as tri-n-butyltin hydride (BDE Sn− H = 79 kcal mol−1,37 k298K = 2 × 106 M−1 s−1)38 and αtocopherol (BDE O−H = 77 kcal mol−1,39 k298K = 6 × 105 M−1 s−1).40 Empirical models have shown that the reactivity of a class of radicals toward a given hydrogen atom donor is well described by two parameters: the activation energy of the thermoneutral reaction (Ee0) and the enthalpy of the reaction of interest (ΔHe).41 Different interactions in the transition state such as polar effects, antibonding (triplet repulsion), or neighboring π-electrons may influence Ee0, which is particularly low for the reactions of alkyl radicals with thiols.10 A remarkable consequence of this low energy of activation even for close to thermoneutral hydrogen atom transfer is the importance of the reverse reaction. Easily available by hydrogen transfer from the corresponding thiols, thiyl radicals are highly reactive toward hydrogen abstractions from weak C−H bonds, the rapid equilibrium between the two fast processes being a key aspect of various chemical and biochemical transformations involving thiyl radicals. Denisov and Chatgilialoglu have already reviewed and discussed the rate constants and Arrhenius equations for the hydrogen abstraction from thiols by different types of radical, and we direct the reader to their work for theoretical insights and additional data.10 The following section mainly focuses on the cases where the reverse reaction becomes significant and on the factors directing the equilibrium. C


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of a β-alkoxy group seems to decrease the rate of hydrogen atom transfer from thiophenol (Table 1, entry 5). The enthalpy of reaction remains an important parameter, and the benzyl radical reacts much slower than alkyl radicals (Table 1, entry 6). Because of the weak S−H bond in thiophenol, the reverse reaction, that is, hydrogen abstraction from hydrocarbons, is generally slow. Nevertheless, the p-chlorophenylthiyl radical was shown to react with ethylbenzene at 103 M−1 s−1 at room temperature.48 Similarly, Bertrand and co-workers reported the isomerization of allylamines into enamines via a reversible hydrogen atom transfer with the phenylthiyl radical.49 Similarly, the highly electrophilic pentafluorophenylthiyl radical and 2,4,6-tris(trifluoromethyl)phenylthiyl radical have been used by Roberts and co-workers to promote isomerization processes via hydrogen abstraction from electron-rich C−H bond (see section 8.1).50 2.2.2.b. Alkanethiols. The equal S−H BDEs in alkanethiols lead to similar reactivity, even if small variations are observed in some cases such as with sterically hindered tertiary thiols (Table 2, compare entries 1 and 2).44 In any case, primary alkyl radicals rapidly abstract a hydrogen atom from alkanethiols at ambient temperature (Table 2, entry 1). Secondary and tertiary alkyl radicals react slightly more slowly probably due to their relative thermodynamic stability. The reverse reaction follows the opposite trend, and the reaction rate becomes significant for hydrogen atom abstractions from tertiary C−H bonds (Table 2, entry 3). Despite being much less exothermic, the reaction of a highly nucleophilic α-alkoxy radical proceeds as fast as that of a primary alkyl radical (Table 2, entry 4). As discussed above, polar effects between the electron-rich carbon-centered radical and the electrophilic thiyl radical counter balance for the lower heat of reaction. Although no kinetic data for the reverse reaction in apolar media are available, hydrogen abstractions from α-alkoxy C−H bonds are certainly accelerated according to the thermodynamic equilibrium. In contrast, the inductive effect of a β-alkoxy group decreases the electron density on the carbon atom carrying the unpaired electron, and the reaction is slower than with a primary alkyl radical despite a comparable heat of reaction (Table 2, entry 5). Although the reaction is almost thermoneutral, acyl radicals are rapidly reduced by alkanethiols, the strong nucleophilic character of acyl radicals probably contributing to favor this reaction (Table 2, entry 6). Despite the lack of kinetic data, the reverse reaction is logically expected to be fast: thiyl radicals are known to rapidly abstract hydrogen atoms from aldehydes, and they have been used as catalysts in radical decarbonylation reactions, as well as in carbon−carbon bond-forming processes (see section 8.1.4).54 If a benzylic radical is involved, the reaction is now endothermic by a few kilocalories per mole: the hydrogen abstraction from an alkanethiol is logically slow, the reverse reaction becoming favored as first shown by Walling with cumene,59 then by Pryor with ethylbenzene (Table 2, entry 7). Electron-donating substituents on the benzyl radical dramatically enhance the reactivity; the hydrogen atom abstraction from benzyl methyl ether is 20 times faster than that from ethylbenzene despite a similar heat of reaction (Table 2, entry 8). Pryor described the relative rate constants for hydrogen atom abstractions by the cyclohexanethiyl radical on various other substrates.57 It is noteworthy that β-metal C−H bonds may undergo hydrogen atom transfer to thiyl radicals.60 To the best of our knowledge, no kinetic value for the hydrogen atom transfer from a thioacid has been reported.

2.2.1. Isotope Effect. According to the proposal that primary hydrogen−deuterium isotopic effect reaches a maximum for a most symmetrical transition state,42 Pryor has shown that kH/kD for hydrogen atom abstraction from tertbutanethiol and thiophenol varies with the enthalpy of reaction, being up to 6−7 for a thermoneutral reaction. For largely exothermic or endothermic reactions (|ΔHr| ≥ 10 kcal mol−1), kH/kD is found to be around 2−4.43 2.2.2. Carbon-Centered Radicals in Apolar Media. 2.2.2.a. Thiophenols. Because of their weak S−H bond dissociation energy, thiophenols are very efficient hydrogen atom donors toward alkyl radicals. Their reactivity is not always greatly affected by substitution on the aromatic ring, and Chatgilialoglu showed that para-methoxy, chloro, or fluoro substituted thiophenols all react with a β-alkoxy primary alkyl radical with rate constants around 108 M−1 s−1 at 80 °C.44 Minor variations were observed but could be correlated neither with S−H BDEs nor with Hammet constants.14 Colle and Lewis studied various substituted thiophenols in reactions with triarylmethyl radicals and observed a modest correlation between the rates of reaction and Taft’s parameters.45 In hydrogen atom transfers between two radicals of different electronegativity, charge transfer configurations may contribute to the character of the transition state, such polar effects resulting in a lowering of the activation barrier.46 In the case of thiyl radicals, the hydrogen atom exchange is favored with electron-rich radicals, while mismatch philicity disfavored the reaction with electron-poor radicals (Figure 1). Polar effects in hydrogen atom transfers from thiols have been well described by ab initio calculations47 and by the intercrossing Morse curves model.10

Figure 1. Examples of match and mismatch philicity in hydrogen atom transfers involving thiyl radicals.

This effect probably compensates for the lower heat of reaction on going from primary to secondary and tertiary alkyl radicals (Table 1, compare entries 1−3). In contrast, the highly electrophilic perfluoroheptyl radical reacts almost 3 orders of magnitude slower, despite a more exothermic reaction (Table 1, entry 4). Similarly, the inductive electron-withdrawing effect Table 1. Rate Constants for the Reduction of Various Alkyl Radicals by Thiophenol in Apolar Media

entry

radical

1 2 3 4 5 6

n-C3H7−CH2 (CH3)2CH (CH3)3C n-C6F13−CF2 ROCH2CH2 PhCH2

kH/[M−1 s−1] (T/K) 1.3 1.0 1.4 2.8 7.6 3.0

× × × × × ×

8

10 108 108 105 107 105

b

(298) (298)b (298)b (303)c (353)d (298)e

ΔHa −17 −15 −12 −20 −18 −5

a In kcal mol−1, calculated using PhS−H BDE = 83 kcal mol−1 and C− H DBE of related hydrocarbons from ref 12. bData from ref 51. cData from ref 52. dData from ref 44. eData from ref 53.

D


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Table 2. Rate Constants for the Reduction of Various Alkyl Radicals by Alkanethiols and for the Reverse Reaction in Apolar Media

entry

radical

thiol

1 2 3 4 5 6 7 8

R−CH2 R−CH2 R3C R−CH(OMe) RCH(OMe)CH2 R−C(O) Ph−CHR Ph−CH(OMe)

t-BuSH RCH2SH RCH2SH RCH2SH RCH2SH RCH2SH RCH2SH R2CHSH

kH/[M−1 s−1] (T/K) 8 2 4 2 1 7 7

× × × × × × ×

106 107 106 107 107 106 102

(298)e (298)b,c (303)b (298)b (298)b (353)f (333)g

k−H/[M−1 s−1] (T/K)

2 × 104 (353)d

1 × 106 (353)d 2 × 107 (353)d

ΔHa −13 −13 −8 −4 −14 −1 +2 +2

In kcal mol−1, calculated using RS−H BDE = 87 kcal mol−1 and C−H DBE of related hydrocarbons from ref 12. bData from ref 55. cData from ref 56. dData from ref 57 using the cyclohexylthiyl radical. eData from ref 58. fData from ref 44. gData from ref 10.

a

Table 3. Rate Constants for the Reduction of Various Alkyl Radicals by Alkanethiols and for the Reverse Reaction in Aqueous Solution

In kcal mol−1, calculated using RS−H BDE = 87 kcal mol−1 and C−H DBE of related hydrocarbons from ref 12. bData from ref 55 using glutathione diethyl ester. cData from ref 67 using penicillamine (PenSH). dData from ref 68. eData from ref 68. fCalculated C−H BDE from ref 69. a

ment in the reactivity, and rate constants for the reduction of a tertiary alkyl radical were found to be enhanced by a factor of 10 in water as compared to the same reaction in dichloromethane (compare Table 2, entry 3 and Table 3, entry 1).55 Newcomb and co-workers proposed that the polar transition state for the reaction of a nucleophilic radical with a thiol is stabilized by polar solvents, thus diminishing the activation barrier for the hydrogen atom transfer.55 The equilibrium constant (K = kH/k−H) between the C- and the S-centered radical should not be affected by the media as long as no particular interaction significantly modifies the enthalpy of reaction.64 Consequently, hydrogen abstractions from hydrocarbons by thiyl radicals are also accelerated in aqueous media. Because of the importance of the latter reaction in living cells, many studies on the reactivity of thiyl radicals in

However, the analogous bond dissociation energy and reactivity as compared to alkanethiols suggest a similar behavior. 2.2.3. Solvent Effects and Hydrogen Atom Transfer in Aqueous Solutions. Many transformations involving polarized radicals are, contrary to a common belief, sensitive to the polarity of the solvent.61 Being comparable protic hydrogen atom donors, phenols (pKa O−H = ∼10) are considerably less reactive toward hydrogen abstractions in polar media due to hydrogen bonding with solvent molecules.62 Thiols, which are rather poor hydrogen-bond donors, are barely sensitive to this effect.63 In contrast, the hydrogen atom transfer to an alkyl radical has been shown to be accelerated in polar solvents and particularly in water. Although almost no difference is observed between toluene and a low polarity solvent such as THF,58 acetonitrile or methanol already induces a significant enhanceE


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aqueous media have been reported. For instance, isopropanol undergoes hydrogen atom abstraction by the thiyl radical derived from penicillamine at a significant rate, although the reduction of the corresponding radical is still considerably faster in accordance with the thermodynamic equilibrium (Table 3, entry 2). As discussed above for benzyl methyl ether, both polar and enthalpic effects make benzyl alcohol a privileged substrate for hydrogen atom transfer to thiyl radicals (Table 3, entry 3). Amino acids derivatives such as sarcosine anhydride (1,4dimethylpiperazine-2,5-dione, SarcA) are also reactive toward thiyl radicals (Table 3, entry 4). In the case of N-acetylalanine, the reaction does not proceed faster than that with isopropanol despite now being exothermic. Mismatching polar effects as well as steric hindrance may contribute in this case to the relatively low reactivity (Table 3, entry 5). Schöneich and coworkers measured the rate constants for the reaction of thiyl radicals with a variety of biologically relevant molecules, for example, thymine (Table 3, entry 6), carbohydrates,65 and different model peptides (see section 8.5).66 2.2.4. Silyl Radicals. The reaction of thiols with silylcentered radicals is interesting to consider because the hydrogen atom exchange proceeds rapidly despite being only weakly exothermic (Scheme 1, kSiH ≈ 5 × 107 M−1 s−1 at 60

Zavitsas and Chatgilialoglu suggested that low triplet repulsion between the two unpaired electrons on the heavy atoms may be a more appropriate explanation for the small energy of activation observed in this reaction.72 2.2.5. Oxygen- and Nitrogen-Centered Radicals. Thiols react very rapidly with hydroxyl (109−1010 M−1s−1)34 and alkoxyl radicals (6 × 107 and 109 M−1 s−1 at 298 K with a primary alkanethiol and thiophenol, respectively) due to the large enthalpy of reaction.10 In contrast, thiols are poorly reactive toward peroxyl radicals, and thiophenol transfers a hydrogen atom to an alkyl peroxyl radical at a rate constant of ∼5 × 103 M−1 s−1 (300 K).73 Newcomb and co-workers studied the kinetics of various reactions involving nitrogen-centered radicals, including their reduction by hydrogen atom donors. Because of the strong corresponding N−H bonds, dialkyl aminyl radicals are rapidly reduced by thiols (5 × 106 and 108 M−1 s−1 at 298 K with tertbutanethiol and thiophenol, respectively),74 whereas the rate constants for the reaction of the corresponding protonated aminium cation radical are approximately halved.75 This trend of reactivity, opposite to that observed with tributyltin hydride, may also reflect the mismatch in philicity with the more electrophilic aminium cation radical. Amidyl radicals appeared to be similarly reactive,76 while iminyl radicals are reduced at rates of about 1 order of magnitude lower.77

Scheme 1

2.3. Addition−Fragmentation Reactions

Many aspects of the anti-Markovnikov addition of thiols to olefins have already been reviewed by Griesbaum in the early 1970s,3b and the reader is directed to this comprehensive review for early examples describing regio-/stereoselectivity issues and products distribution analysis. The following section focuses on the rate constants for addition/fragmentation reactions and on the factors directing them. Synthetic applications will be discussed in section 3. 2.3.1. Influence of the Alkene Structure. The addition of thiyl radicals to unsaturated system is generally a fast and reversible process,78 thereby complicating the kinetic analysis. Considering an irreversible reaction, Sivertz and co-workers reported large rate constants for the addition of a primary alkyl thiyl radical to terminal alkenes (Table 4, entries 1 and 2). The exothermicity of the reaction is a crucial parameter, and styrene reacts in this case at a rate close to the diffusion limit (Table 4, entry 2). Starting from a 2-bromothioether, Chatgilialoglu and co-workers demonstrated the rapid fragmentation of a primary

°C).70 Albeit slower, the reverse reaction does take place at significant rates, making thiyl radicals particularly useful to generate silyl radicals from various organosilanes (see section 8.2). At the highest level of theory (CCSD(T)/6-311G**// MP2/6-311G**), Schiesser and Skidmore computed the reaction of Me3SiH with the methylthiyl radical to be endothermic by more than 7 kcal mol−1, resulting in an equilibrium constant kSH/kSiH of 1.3 × 10−4 at 80 °C.71 Nevertheless, the heat of reaction may have been slightly overestimated, and the hydrogen abstraction from silanes by alkylthiyl radicals was later found by Roberts and Cai to proceed at rate constants around kSH = 104−105 M−1 s−1 at 60 °C.70 As seen above with α-alkoxyl radicals, favorable polar effects between the electrophilic thiyl radical and the nucleophilic silyl radical may rationalize this behavior.46

Table 4. Rate Constants for the Addition of Alkylthiyl Radicals onto Olefins and for the Reverse Reaction

entry a

1 2a 3b 4c 5c 6d 7d

alkene 1-pentene PhCHCH2 ethylene 1-octene (c-C3H5)2CCH2 (E) RCHCHR (Z) RCHCHR

thiol

kadd/[M−1 s−1]

n-BuSH n-BuSH n-OctSH (CH3)3SH (CH3)3SH HO(CH2)2SH HO(CH2)2SH

7 × 10 1.2 × 109

kfrag/[s−1]

6

1.9 2.4 2.9 1.6

× × × ×

106 108 105 105

2.5 × 106 3.4 × 105 1.6 × 108 1.7 × 107

T/K 298 298 298 298 298 295 295

a Data from ref 82. bData from ref 81f, competition experiment starting from the 2-bromothioether. cData from ref 83, from k−1/kH, assuming the rate constant for the reduction of an alkyl radical by an alkanethiol is kH = 107 M−1 s−1. dData from ref 80. Additional data can be found in refs 27, 78, 84.

F


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β-sulfanyl alkyl radical (Table 4, entry 3), while Griller et al. measured a slightly lower rate for the fragmentation of a more stabilized secondary β-sulfanyl alkyl radical (Table 4, entry 4). With this system, the addition rate was found to be in the same order of magnitude as that reported by Sivertz with the nbutylthiyl radical, albeit slightly diminished perhaps because of the steric demand of the tertiary alkylthiyl radical (Table 4, compare entries 1 and 4). 1,1-Dicyclopropylethylene is an excellent radical trap for thiyl radicals, this reaction being irreversible due to the rapid opening of the cyclopropyl ring (Table 4, entry 5). Internal olefins are approximately 10 times less reactive than terminal ones toward the addition of alkylthiyl radicals, whereas the fragmentation of the corresponding β-sulfanyl alkyl radical is accelerated by 2 orders of magnitude (Table 4, entries 6 and 7). The favored anti-conformation of the corresponding βsulfanyl radical makes the fragmentation process stereoselective for the trans olefin,79 and the thermodynamic equilibrium is reached for E/Z = 5 in the case of methyl linoleate (Scheme 2).80

of arenethiyl radicals in the presence of unsaturated compounds was easily monitored. The use of various concentrations of oxygen as a selective trapping agent for the resulting β-sulfanyl alkyl (vide infra) radical allowed the authors to determine both addition and fragmentation rate constants.27 Because of resonance stabilization, arythiyl radicals are 1−3 orders of magnitude less reactive than alkylthiyl radicals in addition reactions onto alkenes (compare Table 4, entry 1 and Table 5, entry 5). Nevertheless, the reaction with styrene is still largely exothermic, and the fragmentation process is barely observed (Table 5, entry 1). 2.3.2. Enthalpy of Reaction versus Polar Effects. In the case of styrene derivatives, a significant rate enhancement is observed for electron donating para-substituents (Table 5, compare entries 1−4). Studying a wide range of substituted styrenes, Ito and Matsuda attributed this behavior to polar effects between the electrophilic thiyl radical and electron-rich alkenes, and a linear relationship (with a negative ρ+ value) in the Hammet plot of the rate of reaction versus σ+ was observed.86 Nevertheless, in the cases of substituted terminal alkenes, a dominant contribution of charge transfer configurations to the character of the transition state would predict a particularly rapid addition onto electron-rich alkenes such as vinyl ethers or acetates. In contrast, electron-deficient acrylate and acrylonitrile derivatives are clearly the most reactive, the reaction rates following the enthalpy of reaction as demonstrated by the linear relationship observed between log(kadd) and log(K) (Table 5, compare entries 5−9).87 Similarly, captodative effects that stabilize the resulting radical adduct may lead to particularly fast addition rates with some 1,1disubstituted alkenes.88 Like most radical addition reactions, the reactivity of cycloalkenes toward thiyl radicals is enhanced by increasing ring strain, which reflects once again the central role of the enthalpy of reaction.89 The effect of substituents on the aromatic thiyl radical may also be well rationalized by the consequent modification of the enthalpy of reaction (see section 2.1.1): a stabilizing para methoxy group results in a slower reaction, while the strongly electron-withdrawing nitro substituent increases the rate constants (Table 5, compare entries 9−12). A similar trend

Scheme 2

Thus, thiyl radicals are very efficient catalysts to promote cis−trans isomerization of olefins (see section 5.1 for synthetic applications), and they have been recently proposed to be responsible for the endogenous formation of trans fatty acids in biological systems (see section 5.1).80,81 The reaction kinetics of arenethiyl radicals have been thoroughly investigated by Ito and co-workers using laser flash photolysis (LFP) of diaryldisulfides.85 Because of their strong absorption in the visible region (vide supra), the decay

Table 5. Rate Constants for the Addition of Arenethiyl Radicals onto Olefins and for the Reverse Reaction in Apolar Solvent at 296 K

a

kadd/[M−1 s−1]

entry

alkene

thiol

1a 2b 3b 4b 5c 6a 7a 8a 9a 10d 11d 12d

PhCHCH2 p-Cl-PhCHCH2 p-Me-PhCHCH2 p-MeO-PhCHCH2 C4H9CHCH2 CH2CH(OAc) CH2CH(OBu) CH2CH(CN) CH2CH(Me)CO2Me CH2CH(Me)CO2Me CH2CH(Me)CO2Me CH2CH(Me)CO2Me

p-ClC6H4SH p-ClC6H4SH p-ClC6H4SH p-ClC6H4SH p-ClC6H4SH p-ClC6H4SH p-ClC6H4SH p-ClC6H4SH p-ClC6H4SH C6H5SH p-MeOC6H4SH p-NO2C6H4SH

2.7 3.9 8.0 1.8 1.5 4.6 1.8 4.6 5.4 3.2 4.6 1.8

× × × × × × × × × × × ×

107 107 107 108 104 104 105 105 106 106 105 107

K = kadd/kfrag/[M−1] >500

0.0001 0.008 0.08 0.5 11 7.8 0.5

Data from ref 87. bData from ref 86. cData from ref 90. dData from ref 36. G


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phenyl acetylene are about 20 times less reactive toward arenethiyl radicals than the analogous acrylate and styrene (Table 6, entries 2 and 3).90 This behavior was rationalized by the lower degree of conjugation of the unpaired electron with the π-substituent in the radical adduct. Studying the addition of substituted arenethiyl radicals onto phenylacetylenes, Ito and co-workers could show that the rate of reaction is largely directed by the enthalpy of reaction; that is, stabilized electrondonating group substituted arenethiyl radicals display a decreased reactivity (Table 6, compare entries 3−5). Electron-donating substituents on the aromatic rings of arylacetylenes tend to increase the rate of addition (Table 6, compare entries 3, 5, and 6).96 The addition of thiophenol to internal 1-phenylalkynes was found to be regio- and stereoselective, the addition leading to the more stable aryl-substituted alkenyl radical intermediate. Montevecchi and co-workers have shown that the kinetically favored Z-isomer could be obtained with high levels of stereocontrol by carrying out the addition with a large excess of alkyne.99 Although the reduction of the linear π radical formed upon the addition of the phenylthiyl radical on phenyl acetylene (R = H) is expected to take place from the less hindered face (i.e., opposite to phenylsulfanyl group), leading to the observed Z-product (Table 7, entry 1), the high Z-

of reactivity was observed with iso-butyl vinyl ether and vinyl acetate. However, in the case of these electron-rich olefins, the difference in reactivity between EWG and EDG-substituted thiyl radicals is much more important than that with acrylonitrile, suggesting the contribution of polar effects to the transition state of the addition of strongly electrophilic arenethiyl radicals to electron-rich alkenes.91 2.3.3. Solvent Effects. The impact of the solvent polarity on the rate of addition of thiyl radicals onto alkenes seems to be rather limited.92 Nevertheless, Ito and Matsuda have shown the rates of addition of para-amino and para-dimethylamino substituted arenethiyl radicals to alkenes are particularly sensitive to the nature of the solvent. This behavior was attributed to the relative (de)stabilization of the thiyl radicals, as illustrated by their solvent-dependent UV−vis absorption band.93 The overall effect results from a delicate balance between hydrogen-bonding and dipole−dipole interactions. 2.3.4. Alkynes. The addition of thiyl radicals to alkynes takes place on the less substituted carbon, giving a vinyl radical. Terminal alkyl-substituted alkynes are as reactive as their alkene counterpart. For instance, competition experiments for the addition of the methanethiyl to 2-propene and 2-propyne demonstrated that the latter reacts only 1.2 times slower than the former at 20 °C.94 The reaction is more exothermic than with alkenes as replacing a very weak π-bond by a stronger Csp2−S σ-bond compensates for the energetic cost of generating a vinyl radical.94 Thus, the reverse reaction that releases the triple bond is rather slow, and fragmentation of the thiyl radical is generally not observed due to the rapid decay of the resulting highly reactive vinyl radical. Nonetheless, elimination of an arenethiyl radical from a β-sulfanyl vinyl radical may be observed depending on the reaction conditions.95 Ito and co-workers reported several rate constants for the addition of arenethiyl radicals to alkynes. The factors directing the rate of reaction are closely related to those described above with alkenes, although some differences are observed. 1Pentyne was found to react with various substituted arenethiyl radicals at rates similar to those observed with 1-hexene (Table 6, entry 1).90 In the case of phenylacetylene, early studies

Table 7. Diastereoselectivity of the Addition of Thiophenol onto 1-Phenylalkynes99

Table 6. Rate Constants for the Addition of Arenethiyl Radicals onto Terminal Alkynes at 296 K

entry

R

1 2 3 4 5 6 7 8

H H Me Me Et Et t-Bu t-Bu

[alkyne] neata 10−1 Mb neata 10−1 Mb neata 10−1 Mb neata 10−1 Mb

initiator

(1 equiv)

AIBN

(1 equiv)

AIBN

(1 equiv)

AIBN

(1 equiv)

AIBN

Z/E 90:10 10:90 90:10 10:90 90:10 50:50 100:0 100:0

Reactions carried out at 100 °C, using a 0.1 M solution of PhSH in the neat alkyne. bReactions carried out in solution in benzene at 100 °C.

a

entry a

1 2a 3a 4a 5a 5b 6b a

alkene

thiol

n-PrCCH CHCHCO2Me PhCCH PhCCH PhCCH p-ClC6H4CCH p-MeOC6H4CCH

p-ClC6H4SH p-ClC6H4SH p-ClC6H4SH p-MeC6H4SH p-MeOC6H4SH p-ClC6H4SH p-ClC6H4SH

kadd/[M−1 s−1] 2 1.5 1.1 3.7 8.1 2.0 6.5

× × × × × × ×

104 104 106 105 104 106 106

selectivity observed in the case of 1-phenylalkyne (R = Me, Et, t-Bu) is more puzzling (Table 7, entries 3, 5, and 7). The favored approach of thiophenol from the side cis to the alkyl chain even in the case of the bulky tert-butyl group (Table 7, entry 7) suggests a peculiar intermediate, in which interactions between the phenylsulfanyl group and the delocalized unpaired electron may completely shield one face, as proposed by Benati, Montevecchi, and Spagnolo.99 The authors showed that the same transformations using equimolar amounts of thiophenol and terminal or internal alkynes in benzene at 100 °C in the presence of AIBN led to a mixture of E/Z vinyl sulfides in high yields (70−80%). Under these conditions, the initially formed Z-vinyl sulfide is probably isomerized into the E-product through reversible addition of the thiyl radical onto the alkene. Here again, the ratio of E/Z-

Data from ref 90. bData from ref 96.

attributed a linear π radical for the α-aryl vinyl radical resulting from the addition of a thiyl radical. The higher resonance stabilization of α-aryl vinyl radicals as compared to the related α-alkyl vinyl radicals is believed to be responsible for the higher reactivity of aryl-substituted terminal alkynes as compared to alkyl-substituted ones.97,98 Nevertheless, methyl propiolate and H


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radical adduct that may then fragment either the attacking radical or a new thiyl radical from the starting disulfide (Scheme 4).108

isomers was strongly dependent upon the nature of the alkyne (Table 7, compare entries 2 and 4). In the case of R = t-Bu, steric hindrance probably prevents further addition of the thiyl radical and isomerization of the vinyl sulfide, the latter being isolated as a single isomer albeit in very low yields under these conditions (Table 7, entry 8). 2.3.5. Conjugated Dienes and Allenes. Terminal conjugated dienes are excellent radical traps, the addition of a thiyl radical resulting in a stabilized allylic radical.100 Ito showed that phenylthiyl radicals react with terminal 1,3-dienes even faster than with styrene (around 3 × 107 M−1 s−1 with butadiene at 296 K). 1,4-Dimethyl substitution at the terminal positions decreases the reactivity, however, only by a factor 4.101 Terminal allenes may undergo the addition of a thiyl radical either at the sp hybridized carbon atom to furnish an allyl radical or at the terminal position.102 1,3-Disubstitutions make the reaction selective for the formation of the allyl radical, the reaction taking place as fast as with terminal ones (ca. 5 × 106 M−1 s−1 with arenethiyl radicals at 296 K).103 2.3.6. Aromatic Systems. Thiyl radicals are generally not reactive toward homolytic aromatic substitutions under classical conditions. Nevertheless, such reaction pathways have been proposed to occur at elevated temperatures (600 °C).4d In contrast, the addition of a thiyl radical to the C6-position of a pyrimidine nucleoside has been proposed to take place under mild conditions, suggesting a new role of thiyl radicals in DNA damaging.104

Scheme 4

On the other hand, thiyl radicals rapidly react with thiolate anions to furnish disulfide radical anions (RSSR−•), which are important intermediates in the oxidation of thiols to disulfides in aqueous media.109 2.4.3. Thiocarbonyl Compounds. Thiocarbonyl compounds are generally excellent radical traps.110 The addition of thiyl radicals onto thiohydroxamic acid derivatives has been used by Barton and co-workers to develop an efficient decarboxylation method using tert-butanethiol (see section 7). For example, the pyridylthiyl radical adds to thiohydroxamic esters at rate constants close to the diffusion limit (Scheme 5).111 Although in these cases, the fragmentation of the N−O Scheme 5

2.4. Reactions of Thiyl Radicals at Heteroatomic Centers

2.4.1. Oxygen. Diverging from the behavior of carboncentered radicals, the reaction of thiyl radicals with oxygen is a reversible process. Although some kinetic studies that neglect this aspect described underestimated rate constants for the addition reaction,105 it has been eventually demonstrated that the process occurs at diffusion-controlled rates, while the resulting thiylperoxyl radical rapidly fragments back an oxygen molecule (Scheme 3, eq 1).106 Thus, in oxygen saturated Scheme 3 bond is favored upon addition of a thiyl radical, on other thiocarbonyl compounds, the reaction is probably reversible, and the fragmentation of the thiyl radical may be too fast to allow other reaction pathways to compete. Such behavior may explain the inefficiency of thiols to promote Barton McCombie deoxygenations using xanthates.110 2.4.4. Phosphites. Alkylthiyl radicals attack the phosphorus atom of a trialkylphosphite; the addition step is followed by a fragmention leading to a thiophosphite and the corresponding alkyl radical (Scheme 6).112 Walling has shown that the reaction of an alkylthiyl radical with a trialkylphosphite radical proceeds very rapidly (2.5 × 108 M−1 s−1 at 353 K), whereas trialkylphosphines are 5 times more reactive.113 In contrast, arenethiyl radicals seem to be almost unreactive, the reaction with trimethylphosphite taking place 5 orders of magnitude slower.87

solvents ([O2] = 10−4−10−3 M), the equilibrium constant (K = kadd[O2]/kfrag) is in the order of unity, allowing efficient processes involving thiyl radicals to occur under aerobic conditions (e.g., TOCO reaction, see section 3.3.1.c). The fate of the resulting thiylperoxyl radical may then unfold in different ways; the rapid oxygen atom transfer reaction to a thiol molecule results in the formation of a sulfenic acid and a sulfinyl radical (Scheme 3, eq 2), while a slow rearrangement furnishes a sulfonyl radical (Scheme 3, eq 3).106,107 As expected from their thermodynamic stability, arenethiyl radicals are less reactive toward oxygen; the rate of addition has been estimated to be around 9 × 104 M−1 s−1 at 296 K, although the reversibility of the process was not taken into account.87 2.4.2. Disulfides. Alkylthiyl radicals rapidly react with disulfides, resulting in the formation of a transient sulfuranyl

Scheme 6

I


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2.4.5. Organoboranes. The homolytic displacement of an alkyl radical on an organometallic compound occurs with a wide range of heteroatom-centered radicals.19,114 Thiyl radicals do not make the exception, and their reaction with trialkylboranes is particularly rapid (8 × 108 M−1 s−1 for nBu3B at 323 K). As for all homolytic substitution reactions on alkylboron derivatives, partially oxidized organoboranes such as Bu2BSBu are less reactive due to the decreased Lewis acidity of the boron center.84b 2.4.6. Miscellaneous. Thiyl radicals can add to an isonitrile to furnish an imidoyl radical. In the case of secondary and tertiary alkanethiols, the imidoyl radical may then undergo fragmentation of an alkyl group to furnish an isothiocyanate and the desulfurized alkyl radical. If primary or aromatic thiols are used, reduction of the imidoyl radical intermediate into the corresponding thioformimidate takes place selectively (Scheme 7).115 Some synthetic applications relying on the use of isonitriles as trapping reagents for thiyl radicals will be discussed in more detail in section 6.

radicals onto the CC bond of alkenes can be achieved both in inter- and in intramolecular fashion. Successful additions of thiyl radicals onto substituted CC bonds have been reported for a wide range of different alkenyl groups, including chloroalkenes,118 fluoroalkenes,119 enol ethers,120 fluoroenol ethers,121 vinylsulfides,122 O- and N-vinylcarbamates,123 vinyl acetates,124 N-vinyl- and N-allyl imidazolium ions,125 vinyltrialkoxysilanes,126 vinylphosphonates127 and vinylphosphonic acid,128 acrylates, and related compounds.124,129 The presence of a heteroatom at the vinylic position of the olefin can lead to the formation of a stabilized or destabilized radical and hence control the regioselectivity of the addition of a thiyl radical, while heteroatoms at allylic positions can potentially lead to fragmentations or rearrangements (see sections 8.1 and 5.2.1.a). The carbon-centered radical resulting from the addition can also be trapped intramolecularly to form cyclic compounds or even intermolecularly with external traps, thus allowing the formation of either two carbon−heteroatom bonds, or a carbon−sulfur bond and a carbon−carbon bond in a single step. The following section illustrates these different aspects. 3.1.1.b. Addition to Simple Alkenes. The addition of thiols to olefins was first reported by Posner in 1905,130 but it was in 1938 that Kharash et al. proposed a free-radical chain mechanism for this process.131 The addition of thiyl radicals to olefins was studied extensively throughout the 1960s, and these early results were summarized in an excellent review by Griesbaum in 1970.3b We do not wish to replicate previous reviews; however, a brief explanation of the basic principles of the reaction follows, as it will aid readers as an introduction to more recent discoveries. As previously discussed in section 2.3, the addition of thiols to alkenes can be initiated by the thermal decomposition of various radical initiators, including cumyl hydroperoxide,131,132 oxygen,133 or the very popular 2,2′-azobis(2-methylpropionitrile) (AIBN). More recently, photoredox catalysis134 proved to be efficient at promoting thiol−ene coupling reactions.135 After initiation (Scheme 8, eq a, initiation step), the thiyl radical adds to the less substituted end of the CC bond to form a carboncentered radical via a reversible process (Scheme 8, eq b, propagation step). The resulting radical can then abstract a hydrogen atom from another molecule of thiol to give the thioether product and a sulfanyl radical, which propagates the

Scheme 7

Thiyl radicals recombine with nitric oxide at almost diffusioncontrolled rate to furnish S-nitrosothiols (RSNO).35 The latter are particularly reactive species and are supposed to be an important nitrosation agent in biological systems.116 Because of the weak S−N bond, nitrosothiols may easily fragment back a thiyl radical upon heating or under light irradiation. Thiyl radicals react with nitrones to form unstable adducts. For example, the thiyl radical derived from glutathione reacts with PBN (α-phenyl N-tert-butyl nitrone) at a rate of 7 × 107 M−1 s−1 at ambient temperature, while the resulting N-oxyl radical fragments at a rate of about 1 s−1.32c Similarly, the reactivity of thiyl radicals with nitroso compounds is reversible, although the addition reaction proceeds with high rate constant (108 M−1 s−1).117

Scheme 8

3. ADDITION OF THIOLS TO CC BONDS 3.1. Addition of Thiols to Simple Alkenes (Inter- and Intramolecular Addition)

3.1.1. Intermolecular Addition: The “Thiol−Ene Coupling” Reaction. 3.1.1.a. General Trends. The most useful synthetic applications of thiyl radicals are based upon their ability to add to carbon−carbon multiple bonds. Since its discovery, the reversible addition of thiyl radicals onto alkenes has been extensively studied. The addition can be carried out under mild conditions, and this efficient reaction proved to be a great tool for the design of materials via “click chemistry” and the preparation of polymers (vide infra). The addition of thiyl J


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chain (Scheme 8, eq c, propagation step). There are a number of possible termination pathways available through recombination of carbon and thiyl radicals (Scheme 8, eqs d−f, termination steps). The regioselectivity of the addition of thiyl radicals to olefins can be explained in terms of the heat of formation or by the enhanced stability of the intermediate carbon-centered radical132b,136 upon addition of the thiyl radical to the less substituted olefinic carbon atom. Although being highly regioselective, the addition of thiyl radicals to linear olefins generally exhibits poor stereoselectivity. In the case of cyclic olefins such as sterically hindered norbornene or norbornadiene,137 as well as with substituted cyclohexenes, stereoselective reactions are possible. In the case of substituted cyclohexenes, the addition occurs preferentially in an anti fashion as the result of a kinetically favored axial attack of the thiyl radical onto the cyclic alkene in its half-chair conformation together with a stereoselective hydrogen abstraction from the thiol into an axial position.118b,138 This aspect is illustrated by the stereoselective addition of thiolacetic acid onto 1-methyl-4tert-butylcyclohexene (Scheme 9, eq a).118b Similarly, thiol−ene

Scheme 10

Scheme 9

quinine 1 and mercaptopropylsilanized silica gel 2, initiated by AIBN (Scheme 10, eq b).144 Polymer-bound chiral (Salen) manganese complexes for heterogeneous asymmetric Jacobsen epoxidation have also been prepared by introduction of a spacer via the free-radical addition of 2-mercaptoethanol onto the styryl moiety of 3 (Scheme 10, eq c).142 The thiol−ene coupling reaction is also ideally suited to peptide chemistry. Unnatural amino acids and peptides can be quantitatively obtained by addition of thiols onto allyl derivatives of natural amino acids.145 For instance, methanethiol adds to unprotected α-allylglycine in dioxane/water or methanol/water in the presence of substoichiometric quantities of 2,2′-azobis(2-mehylpropionitrile) (AIBN) as a radical initiator (Scheme 11, eq a).146 In the reaction with unprotected α-allylglycine, partial racemization of the addition product is observed under these reaction conditions, and the extent of racemization depends upon the nature of the thiol used for the addition process (for a discussion on hydrogen abstractions by thiyl radicals from activated positions, see sections 8.1 and 8.5). Similarly, S-glycosyl amino acids can be prepared from alkenyl glycines by addition of glycosyl thiols.147 For instance, Sglycosyl amino acid 6 was obtained from glycosyl thiols (1.2 equiv) and highly epimerizable vinyl glycine 4 upon photochemical activation in the presence of 2,2-dimethoxy-2phenylacetophenone (DPAP) as the photoinitiator (Scheme 11, eq b).147 This approach also proved to be successful in

coupling (TEC) reactions with methylenecyclohexenes afford predominantly the equatorial products as a result of an axial hydrogen abstraction from the thiol by the carbon-centered radical (Scheme 9, eq b).138b The thiol−ene coupling reaction proved to be extremely useful to prepare insoluble polymer-supported catalysts139 or to link catalysts to soluble dendrimeric skeletons, which can be recovered by precipitation or filtration if the size of dendrimer allows it.140 For example, Oda and co-workers have used a thioether spacer group in the synthesis of polymer-supported quinine catalysts.141 Addition of mercaptoethanol or 3mercaptopropionic acid onto the CC bond of quinine, initiated with AIBN, inserted the spacer group, which was then used to attach the polymeric support (Scheme 10, eq a). These catalysts were found to be more active and led to increased levels of enantioselectivity in Michael additions, conjugated addition reactions, and methanolysis reactions, when compared to the equivalent catalyst without a spacer group. Similarly, mercaptoethanol has been introduced as a spacer group via a thiol−ene reaction in polymer-bound (Salen)manganese catalysts for epoxidation142 and polymer-bound cinchona alkaloids for asymmetric dihydroxylation reactions.143 A further development has seen the attachment of cinchona alkaloids to silica gel, again for use as catalysts in dihydroxylation reactions. This was achieved through the thiol−ene reaction between K


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position might result in a total failure of the coupling reaction, and the reaction conditions have to be chosen with care. With this respect, a proper choice of the reaction conditions and protecting group (in the case of allyl amines) will ensure good yields in most cases. The nature of the thiol (alkyl or aryl thiol, silanethiol) also plays a role, but the choice of the target does not always allow for flexibility. Mild conditions such as irradiation at room temperature in the presence of a photosensitizer proved to be among the best reaction conditions to reach this goal. In this context, the free-radical addition of thiols to olefins has seen much use in carbohydrate chemistry due to mild reaction conditions and tolerance of a wide range of functional groups. As was already mentioned, two different strategies have been employed to achieve a thiol−ene coupling reaction using carbohydrate derivatives, depending on which of the two partners the thiol moiety is located. The most widely used approach consists of adding a thiol onto a carbohydrate derivative having a carbon−carbon double bond. The latter can be either located inside the cyclic system (e.g., dihydropyran derivatives, vide infra) or linked to one of the hydroxyl groups. The addition of thiyl radicals to allyl glycosides has seen much interest, since it was first reported in 1974.153 Vliegenthart and co-workers reported the addition of a number of alkanethiols to protected allyl glycosides, including glucose and fructose derivatives, as well as disaccharides.154 In all cases, the addition proceeded in good yields (71−98%) at 75 °C in 1,4-dioxane in the presence of substoichiometric quantities of AIBN (Scheme 12, eq a). Installation of an anomeric 3-

Scheme 11

accessing the more challenging S-linked protein glycoconjugates, for which mutations are sometimes needed to increase the stability of the protein upon UV−light irradiation, as well as S-linked virus-like particule Qβ.148 The coupling can also be achieved via the “reverse” addition, the thiol−ene coupling of a cysteine derivative having a free sulphydryl group with an alkene.149 This type of coupling reaction proved to be successful for peptide and protein glycosylation by using terminal alkenes of C-linked glycosides.150 Glycosylated Lcysteine-N-carboxyanhydride monomers have been prepared via the coupling of N-protected L-cysteine with terminal alkenes derived from C-linked glycosides, and used in living polymerization to access glycopolypeptides.151 Because the allylic position is activated toward hydrogen atom abstraction (see section 8.1), the addition of thiyl radicals onto allyl ethers, allyl amines, or allyl thioethers is not always as simple as it seems at first glance, and unexpected changes in the regioselectivity and/or degradation can sometimes find their origin in the migration of the CC bond next to the heteroatom. For instance, the product resulting from the addition of methane thiyl radical at the internal position of the CC bond in allyl alcohol has been observed in some cases.152 Its formation presumably arises from the addition of the thiyl radical onto the enol ether resulting from the migration of the carbon−carbon double bond (see section 8.1.1, Scheme 249) with the usual and excellent regioselectivity (vide infra) rather than a lack of control in the addition onto the terminal alkene of allyl alcohol. Deprotection of allylamines has been achieved in high yields through the migration of the CC bond followed by ionic addition of the thiol onto the resulting enamines and subsequent cleavage of the thioaminal moiety upon aqueous workup (see section 8.1.2).49b Similarly, the addition of glycosyl thiols onto S-allyl cysteine has been reported to give low yields, even under very mild reaction conditions (photochemical initiation), while the reaction carried out on related S-butenyl peptides gave the coupling products in high yields.147 Because the introduction of an allyl group via alkylation of a heteroatom is very easy to achieve, this approach to prepare functionalized alkenes as partners for a thiol−ene coupling is extremely attractive, and, as a result, numerous examples of such couplings have been reported. However, the practitioner has to keep in mind that side reactions resulting from hydrogen abstraction at the allylic

Scheme 12

mercaptopropanol linker in oligosaccharides, to facilitate purification and separation, can be readily achieved by condensation of allyl ethers or allyl esters with glycosyl thiols upon UV−light irradiation at 250 nm (Scheme 12, eq b).155 The Withers group reported the preparation of a library of lipophilic iminosugars based upon the free-radical addition of thiols such as 8 onto allylamine 7, prepared in seven steps from D-xylose (Scheme 13). The adducts were obtained in moderate to good yields (38−67%, 16 examples) for the reactions carried out in refluxing methanol in the presence of AIBN as a radical initiator.156 In this case, the formation of the desired products L


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magnetite superparamagnetic nanoparticles as a proof of concept for surface coating. The addition of thiyl radicals onto 2,3-unsaturated glycosides such as 12 proceeds with variable levels of regioselectivity depending on the thiols; however, excellent levels of regio- and stereoselectivity have been observed in the addition of some glycosyl thiols, the addition taking place preferentially at the C2 position through the axial attack of the thiyl radical (Scheme 15).120k The absence of epimerization at the anomeric position

Scheme 13

Scheme 15

might be complicated by degradation of the allylamine precursor as well as epimerization of the heteroatomsubstituted chiral centers. Garrell and co-workers reported a very efficient approach to introduce trialkoxysilane functionalities by condensing either 3mercaptopropyltrialkoxysilanes with terminal alkenes or, alternatively, thiols with allyltrialkoxysilanes. The reactions were carried out under neat conditions (or in solution in the minimum of solvent, if required) and upon irradiation with a low power 15 W black light (λmax = 368 nm) in the presence of a small amount (2 mol %) of 2,2-dimethoxy-2-phenylacetophenone (DPAP) as the photosensitizer. Under these mild reaction conditions, excellent yields and high levels of purity were obtained for the addition of 3-mercaptopropyltrialkoxysilanes 9 and 11 onto a range of sensitive alkenes 10 with respect to the hydrogen abstraction (Scheme 14, eqs a− f).157 The trialkoxysilanes thus obtained have been used without any further purification for the functionalization of

supports the lack of migration of the CC bond through hydrogen abstraction from the activated position during this addition process. The thiol−ene coupling reaction has found numerous applications in carbohydrate chemistry.5b For instance, this approach proved to be very useful to introduce new functionalities onto O-per-allylated cyclodextrins.158 Roque and co-workers prepared from cyclodextrins polyanionic and polyzwitterionic compounds as potential inhibitors of HIV transmission,159 while Stoddart and Fulton used the thiol−ene methodology to decorate O-per-allylated cyclodextrins with glycosyl thiols to access carbohydrate clusters (Scheme 16).160 The thiol−ene reactions often conform to Sharpless’s definition

Scheme 14

M


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of properties and the development of initiator free conditions. More recently, attention has turned to the selective functionalization and modification of molecular structures, and thiol−ene polymerization is once again at the forefront of polymer technology. The thiol−ene polymerization process is particularly promising as thiols will copolymerize with almost any olefin, thus allowing products to be developed with tailored physical and mechanical properties. The reaction also proceeds with very high conversion and is relatively insensitive to oxygen when compared to other free-radical polymerization processes. The products generally display uniform cross-link densities, excellent chemical, oxidative, thermal, and light stability, and good water absorption resistance. The kinetics of thiol−ene polymerization processes have been extensively studied, and two basic rules have been established.5d,171 First, the overall conversion rate is directly proportional to the electron density of the olefin, with electronrich olefins reacting most rapidly. Second, of the three common thiol types used in polymerization reactions (Figure 2),

Scheme 16

of “click” chemistry as the reaction is “modular, wide in scope, give very high yields, generate only inoffensive byproducts that can be removed by nonchromatographic methods and be stereospecific (but not necessarily enantioselective).”161 This aspect of the reaction has recently been reviewed by Dondoni, especially with respect toward materials for bioorganic chemistry.5a,b In this respect, the thiol−ene reaction has been used to build up to fourth generation dendrimer cores based upon cross-linked thioethers, which can be further functionalized to give useful supramolecular structures.162 Radicalmediated thiol−ene coupling reactions have also proved to be a useful tool for surface modification, and numerous applications have emerged within the last 5 years. For instance, polymer coatings prepared via chemical vapor deposition (CVD) polymerization and presenting a reactive alkenyl side chain have been coupled with thiols (such as the thiol-terminated cysteine of GRGDYC, a cell-adhering peptide) under photochemical initiation.163 UV-light irradiation coupled with the use of a photomask allows for the modifications of selected areas of the surface. 3.1.1.c. Polymerization Processes with Simple Alkenes. Although less reactive than carbon or oxygen-centered radicals, thiyl radicals have been used to initiate free-radical polymerization processes164 and have also seen use as chain-transfer reagents in living polymerization processes.165 The polymerization of alkenes in the presence of thiols,166 or linear and cyclic disulfides,167 has been extensively studied. Without doubt, the most important commercial application of thiol−ene chemistry has been in photoinitiated polymerization processes. A detailed account of polymerization processes is beyond the scope of this Review; however, a brief discussion follows. We point readers in the direction of thorough reviews of this important aspect of the thiol−ene reaction, published in 1993168 and 2004,169 as well as more recent ones covering the most important updates in the field of polymerization, design of materials, and glycoconjugation.5a,b,d,170 In the late 1970s, the emergence of thiol−ene polymerization chemistry paved the way to new functional materials; however, the emergence of low-cost acrylate monomers curtailed the development of this process. Historically, research focused upon optimization of the conditions for polymerization reactions to furnish cross-linked products with a wide range

Figure 2.

mercaptopropionate esters react at an increased rate when compared to mercaptoacetate esters, which in turn react more quickly than simple alkyl thiols. The use of diene and dithiol (or 1,2-cyclic dithianes) monomers leads to linear polymers, whereas the use of tri- or tetra-substituted monomers results in the formation of cross-linked polymer networks. Recently, interest in the use of the thiol−ene reaction in the modification of polymer backbones has been rejuvenated especially with respect to the incorporation of biologically inspired side chains to make functional biomaterials. Thiol−ene polymers have found applications in a wide variety of materials, including surface coatings, thermosets, protective coatings (clear and pigmented), ceramics, oil coating of metals, liquidcrystalline structural materials, adhesives, and optical components. 3.1.1.d. Addition to Enol Ethers, Vinyl Sulfides, and Related Compounds. Thiyl radicals add onto enol ethers,120a,172 alkenyl acetates,124 and N-vinyloxycarbonyl derivatives123 in a highly regioselective manner, the addition taking place exclusively at the remote position from the oxygen atom. For instance, the free-radical addition of thiols onto D-glucal derivatives generally leads to a single regioisomer, as illustrated by the cumene hydroperoxide (CHP)-initiated thiol−ene coupling between thiolacetic acid and D-glucal triacetate 13 (Scheme 17, eq a).172b However, the addition process onto Dglucal triacetate proved to be only moderately stereoselective, with only a slight preference120a,172b for the formation of the product resulting from the kinetically controlled axial attack of the thiyl radical onto the enol ether in its half-chair conformation. The minor isomer results from the passing through the higher energy twist-boat transition state. Similar results have been obtained for the addition of ethanethiol and propanethiol under photochemical activation, which proceed with a complete lack of selectivity.120a On the other hand, excellent levels of stereoselectivity are typically obtained in the addition of thiols onto exocyclic glycals,120b as a result of the stereoselective hydrogen abstraction from the thiol by the anomeric carbon-centered radical intermediate in its preferred N


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2,3,4,6-tetra-O-acetyl-2-hydroxy-D-glucal upon photochemical activation.120a Very recently, Borbás and co-workers extended the scope of this reaction to include primary and secondary thiols derived from amino acids, peptides, and sugars, thus allowing a convenient access to S-linked glycoconjugates. As was observed for the coupling with ethanethiol and propanethiol,120a the addition of the thiyl radical and the hydrogen abstraction from the thiol by the carbon-centered radical both proceed with excellent levels of stereoselectivity with 2-acetoxyglycals such as 17 (Scheme 18, eq a),120k while only moderate

Scheme 17

Scheme 18

conformation (vide infra).173 Marra, Dondoni, and co-workers showed that the scope of this addition reaction onto glycals could be extended to include glycosyl thiols, thus allowing the preparation of S-disaccharides with moderate to excellent levels of stereoselectivity depending upon the glycal used in the thiol−ene coupling reaction.120j Gervay and co-workers studied the addition of thiolacetic acid to exocyclic glycals derived from D-glucose and L-fructose and showed that only equatorial thiomethyl glycosides are obtained in refluxing benzene in the presence of 2,2′-azobis(2-methylpropionitrile) (AIBN) as a radical initiator (Scheme 17, eq b).120b Peracetylated glycosyl thiols such as 15 add to enol ethers such as hex-5enopyranosides 14 and pent-4-enofuranosides 16 upon irradiation at room temperature in the presence of substoichiometric amounts (typically 10 mol %) of 2,2-dimethoxy-2phenylacetophenone (DPAP) to give the corresponding adducts in high yields (Scheme 17, eqs c,d).120i These reaction conditions limit the choice of protecting groups to those that are stable upon irradiation in the presence of thiyl radicals, and, as a result, only degradation was observed with Operbenzylated sugars.120iThe free-radical addition of thiols onto pent-4-enofuranosides presenting a phosphate moiety at the 3′-position initiated by thermal decomposition of di-tertbutyl peroxalate at 40 °C resulted in the formation of elimination products via the formation of a 3′,4′-radical cation intermediate.120c−e The regioselectivity of the addition of thiols to glycals can be reversed by the presence of an O-acetyl substituent at the C-2 position, as demonstrated by Kushida and co-workers who reported the addition of ethanethiol and propanethiol to

levels of stereoselectivity are observed in the reaction with pentose-derived 2-acetoxy-glycals such as 18 (Scheme 18, eq b).120k In some cases, the choice of solvent proved to have a significant influence on the yields (Scheme 18, eq a). Polyvinylethers, such as 19 and 20, have been used in thiol− ene photopolymerizations with polythiols, such 21 and 22 (Figure 3).120g,h The addition of thiyl radicals onto vinyl sulfides is also a very fast and highly regioselective process.174 This reaction is of great importance because it constitutes the second steps of the

Figure 3. O


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thiol−yne coupling, which is gaining significant interest in the field of material science (see section 4.2). 3.1.1.e. Addition to Chloro- and Fluoroalkenes. Similar to the addition onto enol ethers, free-radical thiol−ene coupling with chloroalkenes proceeds in a regioselective manner, the attack of the thiyl radical taking place at the remote position of the halogen atom (Scheme 19).

Scheme 22

Scheme 19

In the case of cyclic olefins, stereoselective anti additions have been observed (vide infra). This is the case for the addition of thiols (e.g., methanethiol, benzylmercaptan, hydrogen sulfide, thiolacetic acid) to 1-chloro-cyclohexene,175 2chloro-4-tert-butylcyclohexene,118 and other related and conformationally locked chlorocyclohexenes.176 With these susbtrates, a clear preference for the trans-diaxial addition has been noted, especially at low temperatures, presumably as a result of a stereoelectronic control (Scheme 20). Because of the

UV-light or X-ray initiation to give a mixture of 1:1 and 2:1 adducts. Motherwell and co-workers developed a strategy for the synthesis of difluoromethylene-linked C-glycosides from exocyclic 1,1-difluoroenol ether such as 23, and reported that the addition of thiophenol in the presence of benzoyl peroxide occurs regioselectively at the CF2-carbon atom (Scheme 22, eq b). Like in other sugar-related systems, hydrogen abstraction from the thiol took place with a high level of stereselectivity, delivering C-glycoside 24 as a single diastereoisomer.121 On the other hand, a complete reversal in the regioselectivity was observed for the addition of trifluoromethanethiol119a and hydrogen sulfide119b onto the simple 1,1-difluoroethylene (Scheme 22, eq c). 3.1.1.f. Addition to Vinyl Silanes. Free-radical additions of thiols onto vinylsilanes and vinylsiloxanes occur with the classical anti-Markovnikov regioselectivity. For instance, 2-[(2(triethoxysilyl)ethyl)thio]aniline 25 has been prepared by addition of 2-mercaptoaniline onto triethoxyvinyl silane upon heating at 170 °C in the presence of AIBN under neat conditions (Scheme 23). Subsequent immobilization of 25 on silica could then be achieved by refluxing a solution of 25 in toluene in the presence of activated silica.177

Scheme 20

reversibility of the addition step, not only the nature of the thiol (the rate constants kadd, kfrag, and kH for the addition, fragmentation, and hydrogen atom abstraction steps, respectively, are all a function of the thiol), but also the temperature and the molar ratio of the reactants play a role in the stereoselectivity observed, the products resulting from the axial attack being favored under kinetic control. As was observed with carbon-centered radicals,136 the regioselectivity for the free-radical addition onto 1,1-difluoro and 1,1,2-trifluoroolefins strongly depends upon the structure of both the alkene and the thiol, and both modes of addition have been reported (Scheme 21).

Scheme 23

Scheme 21 Divinylsiloxane 26 could be coupled with PEG-thiol 27 in high yield upon irradiation in the presence of 2,2-dimethoxy-2phenylacetophenone (DPAP), provided that the reaction was carefully degassed prior to irradiation (Scheme 24, eq a).126a The thiol−ene coupling has been used to functionalize polyhedral oligomeric silsesquioxanes (POSS) bearing vinyl silanoxane moieties at the periphery.126b,d,178 Dondoni, Marra, and co-workers showed that cysteine-containing peptides and C-glucosylpropylthiol such as 29 add efficiently onto the eight vinylsiloxanes moieties of POSS 28 upon irradiation (λmax = 365 nm) in the presence of a 2,2-dimethoxy-2-phenylacetophenone (DPAP). The presence of a spacer between the sulfhydryl group and the sugar proved to be crucial to

For instance, the addition of thiophenol and ethyl thioglycolate onto alkyl- and aryl-substituted 1,1-difluoro olefins proceeds in both cases with complete regioselectivity, the addition of the thiyl radical taking place exclusively at the CF 2 carbon atom (Scheme 22, eq a). 119c The same regioselectivity is observed for the addition onto 1,1difluoroenol ethers121 and trifluorovinyl methyl ether. Harris and Stacey showed that hydrogen sulfide119b and trifluoromethanethiol119a react with trifluorovinyl methyl ether upon P


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Scheme 24

Scheme 25

Scheme 26

facilitate the approach of the thiyl radical (Scheme 24, eq b).126d A similar strategy has been used to achieve the functionalization of vinyl silica for the preparation of new stationary phases presenting amino acids as zwitterionic species for hydrophilic interaction liquid chromatography (HILC). In this case, the thiol−ene coupling was carried out in MeOH/ H2O under thermal initiation with AIBN.126c 3.1.1.g. Addition to Conjugated Alkenes. Despite their electrophilic nature, thiyl radicals also add onto electron-poor alkenes such as acrylates and related compounds. In the addition onto acrylamides, high levels of stereoselectivity can be obtained, even in acyclic systems. For instance, the addition of thiophenol onto chiral acrylamide 30 derived from (R, R)-2,5diphenylpyrrolidine could be achieved in high yield and with an excellent level of diastereoselectivity (dr = 25:1) in toluene at 100 °C in the presence of AIBN as a radical initiator (Scheme 25, eq a).129 The free-radical addition of thiols onto vinyl phosphonates127,179 and vinyl phosphonic acids128 (Scheme 25, eq b) has also been reported. 3.1.1.h. Application of the Thiol−Ene Reaction in Total Synthesis. The introduction of a sulfanyl group in the structure of a molecule allows for further functionalizations such as the introduction of a CC bond (via the thermal elimination of the sulfoxide or Julia olefination from the corresponding sulfone), a CO bond (Pummerer oxidation), or a C−C bond (via sulfur−lithium exchange, or via the formation of a carboncentered radical).180 Knapp and co-workers reported a total synthesis of griseolic acid B that involved the free-radical addition of thiophenol onto the sterically hindered enol ether moiety of advanced intermediate 32 (Scheme 26). The addition gave temporary protected 33 as a masked enol ether, which could be elaborated further via conversion of the acetonide moiety into the corresponding diacetate 34 followed by the stereoselective introduction of the N6-benzoyladenine to give 35. The enol ether was recovered by oxidation of the thioether 35 to the corresponding sulfoxide, followed by thermal elimination in the

presence of N6-benzoyladenine to limit the competing depurinylation.120f In their approach to integramycin, Wang and Floreancig used the addition of thiophenol onto optically enriched homoallylic alcohol 37 to prepare thioether 38 as a precursor for organomagnesium 39. Condensation of the latter with lactone 40 followed by acidic treatment led to C16−C35 fragment 41 of integramycin (Scheme 27).181 3.1.2. Intramolecular Addition. The addition of thiyl radicals to alkenes can also occur in an intramolecular fashion, thus leading to sulfur heterocycles. On the basis of stereoelectronic factors, 5-exo-trig cyclization processes should be favored over the corresponding 6-endo modes. However, because of the reversibility of the addition of thiyl radicals onto alkenes, six-membered rings can be formed preferentially Q


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of the temperature on the regioselectivity was observed.182a−c Under these reaction conditions, the six-membered rings are formed preferentially over the seven-membered rings for the reactions carried out at 80 °C, while the larger rings are obtained as the major compounds at −65 °C (Scheme 28, eq c). The concentration also proved to influence the product distribution. Unlike the related allylic amines (X = NR),185 compounds 44 (X = O, S, CH2) underwent cyclization without competitive hydrogen abstraction from the allylic position. This strategy was recently applied by the Scanlan group to the preparation of thiosugars as inhibitors of glycosidases.186 For instance, the cyclization of 45 was achieved under mild conditions (UV-light irradiation of a solution of 45 in DMF at room temperature in the presence of 10 mol % of 2,2dimethoxy-2-phenyl-acetophenone (DPAP) as a radical initiator and 10 mol % of 4-methoxy-acetophenone (MAP) as a photosensitizer). Under these mild reaction conditions, endocyclization product 46 was obtained as the major compound, together with small amounts of exo-cyclization product 47 (Scheme 29).186a

Scheme 27

Scheme 29

over five-membered rings. Surzur and co-workers have extensively studied the cyclization of alkenyl mercaptans,182,183 and they showed that pent-4-enylthiyl radical 43, generated from the sulfide 42 upon UV-light irradiation, cyclized to give a mixture of both five- and six-membered rings, with the sixmembered rings being formed preferentially (Scheme 28, eq Scheme 28 Allylic mercaptans are known to be unstable and can polymerize to the polysulfide thiols. 1,4-Dithianes have been obtained by irradiation of a solution of prenyl mercaptan in nhexane. Upon irradiation, dimerization of prenyl mercaptan 48 occurs, leading to 49, which undergoes 6-exo-trig cyclization to give 50 (Scheme 30).187 As was observed by Surzur and coScheme 30

workers in related systems (vide supra),182b no hydrogen abstraction from the allylic position is observed with allyl sulfides, while this competitive process complicates the cyclization of the related allyl amines (see section 8.1.2).185 The thermal rearrangement of methallyl-3-quinolyl sulfide 51 led to a mixture of tricyclic quinoline derivatives 52 and 53, as a result of a competition between ionic and radical pathways.188 The radical cyclization carried out in the presence of a radical initiator, such as oxygen or benzoyl peroxide, or, alternatively, promoted upon UV-light irradiation, gave 53 selectively through a 6-endo-trig cyclization process, while the acidcatalyzed thermal thio-Claisen rearrangement189 in the

a).182a,d The formation of a mixture of compounds resulting from 5-exo-trig and 6-endo-trig cyclization processes has been attributed to the reversibility of the addition step. On the other hand, highly regioselective processes have also been observed for the formation of thia-6-bicyclo[3.2.1]octane (Scheme 28, eq b).184 In the cyclization of thiols of the general structure CH2 CH−CH2−X−(CH2)2−SH (X = O, S, CH2), a dramatic effect R


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presence of pyridine−HCl produced selectively compound 52 (Scheme 31).

Scheme 33

Scheme 31

In the mid 1970s, Maki and Sako reported intramolecular thiol−ene coupling reactions of penicillin derivatives. Upon irradiation in acetonitrile, penicillin derivative 54 led to 3methylenecepham methyl ester 55 and 3-methyl-2-cephem methyl ester 56 (Scheme 32, eq a).190 The dilution proved to Scheme 32

Shortly afterward, Gordon and co-workers reported similar results for the reactions carried out in CH2Cl2 or MeOH except that, instead of regioisomers similar to 56, reduced compound 62 was obtained (Scheme 34).192a The product distribution Scheme 34

have a dramatic effect on the course of this cyclization process, as β- and α-(benzothiazoylthiomethyl)penam derivatives 57 and 58 were formed preferentially at higher concentration (Scheme 32, eq b).191 The proposed mechanism for the formation of 55 and 56 involves homolytic cleavage of the sulfur−sulfur bond in disulfide 54, followed by 6-endo-trig cyclization and subsequent hydrogen abstraction, presumably by thiyl radical 60, to form regioisomers 55 and 56 (Scheme 33, eq a)190 The authors proposed that, at higher concentration, intermolecular addition of photogenerated thiyl radical 60 competes with the photocleavage, thus leading to carbon-centered radical 61, which undergoes homolytic substitution at the sulfur atom to give penams 57 and 58 and thiyl radical 60 that sustains the radical chain (Scheme 33, eq b).191 Alternatively, the sixmembered ring could also result from a sequence involving a 5exo-trig cyclization, followed by an intramolecular homolytic substitution at the sulfur atom (vide infra).192

depending upon the solvent used for these photochemical reactions can be attributed to the better hydrogen-donor ability of CH2Cl2 and MeOH with respect to CH3CN. Cabri and co-workers have extensively studied the transition metal-mediated version of this reaction.192b Initially, they found that both Fe(III) and Mn(III) could promote this reaction and later developed catalytic versions, using the same metals (Scheme 35, eq a).193 They have also developed catalytic Fe(III)−Cu(II) and Mn(III)−Cu(II) variants, which furnished α-methyl-substituted penicillin such as 66 in a highly stereoselective manner (Scheme 35, eq b).194 In the initial work of Maki, the cyclization was proposed to occur through a S


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Scheme 35

Scheme 36

6-endo process. Gordon192a and Cabri later proposed a 5-exo cyclization, followed by rearrangement to give 67 as a common intermediate for five- and six-membered ring formation. Large-membered rings can also be formed using the thiol− ene reaction, and this approach has been applied to the preparation of cyclic peptides on-resin.195

allylic radical resulting from the addition onto 1,3-pentadiene leads to a mixture of 1,2- and 1,4-adducts (Scheme 36, eq d). The same factors account for the observed regioselectivity with 2,5-dimethyl-2,4-hexadiene, for which the 1,2 adduct is formed preferentially (Scheme 36, eq e).199 Higher levels of regioselectivity are generally obtained with arenethiols such as thiophenol than with alkanethiols. Diethyldithiophosphoric acid (EtO)2P(S)SH also proved to add to a variety of 1,3dienes in a regioselective manner.137d Delmond and co-workers developed an approach to theaspiranes based upon the regioselective introduction of a phenyl thioether at the terminal position of the dienyl moiety of γ-pyronene 31 (Scheme 37, eq a).200 The phenyl thioether substituent was then oxidized into the corresponding sulfoxide, which allowed for further functionalization. Similarly, the addition of thiophenol and ethanethiol onto δ-pyronene could be achieved in high yields; however, the addition proved to be poorly regioselective, leading to a mixture of allylsulfides (Scheme 37, eq b).201

3.2. Addition onto 1,3-Dienes

The addition of thiols onto 1,3-dienes has been known since the early work of Posner, who reported the addition of thiophenol to 1-phenyl-1,3-butadiene.130 Later, the regioselectivity of the addition process was studied with other dienes, including 2,3-dimethyl-1,3-butadiene, 100,196 1,3-butadiene,100,197 3-methylenecyclohexene,198 1,2-dimethylenecyclohexane,198 2-methyl-1,3-butadiene (isoprene),100 2-chloro-1,3butadiene,100 and 1,3-pentadiene (piperylene).100 The addition of thiophenol generally takes place at room temperature even in the absence of any added radical initiator, albeit with a very slow reaction rate, whereas other thiols such as thiolacetic acid and alkanethiols usually do not react without thermal or photochemical activation. The addition onto 1,3-dienes can lead to 1,2- and/or 1,4-adducts, and the regioselectivity of this addition process has been the subject of extensive studies.100,197,199 In most cases, the major compound is the 1,4adduct, as the result of a regioselective addition of the thiyl radical at the terminal position of the diene, thus leading to an allylic radical intermediate. The latter then abstracts a hydrogen atom from the thiol, regioselectively at the less substituted position, leading to the more stable internal olefin (Scheme 36, eqs a−d). Addition onto nonsymmetrical 1,3-dienes (such as isoprene) gives a mixture of products resulting from the addition at the two terminal positions (Scheme 36, eq c), while nonregioselective hydrogen abstraction by the 1,3-disubstituted

3.3. Cascade Reactions

3.3.1. Intermolecular Trapping of the Carbon-Centered Radical. 3.3.1.a. Carbon Monoxide. In the early 1950s, polyketones of high molecular weight were prepared via the radical-mediated copolymerization of ethylene and carbon monoxide.202 The polymerization process could be suppressed when the reaction was carried out in the presence of a thiol, the carbon-centered radical (alkyl or acyl) being trapped by T


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Scheme 37

Scheme 38

reactivity of 1,3-dienes, as diphenylthioethers and without incorporation of the phenylselenyl moiety (Scheme 39).205b Scheme 39

hydrogen abstraction from the thiol. For instance, the addition of ethanethiol onto propylene at 130 °C under a high pressure of carbon monoxide (3000 atm) and in the presence of di-tbutylperoxide led to 3-ethylmercapto-2-methylpropanal (16%) and ethyl-n-propylsulfide (50%).203 Yoshida, Isoe, and coworkers have shown that no carbonylation took place at 100 °C in benzene under lower pressure (80 atm) of carbon monoxide.204 3.3.1.b. Chalcogenation. Ogawa, Sonoda, and co-workers developed a chalcogenation reaction, which takes advantage of the high reactivity of thiyl radicals toward alkenes together with the high reactivity of diselenides to trap carbon-centered radicals through a homolytic substitution SH2.205 The use of a binary system (PhS)2/(PhSe)2 allows circumnavigation of the poor reactivity of selenium-centered radicals toward olefins and the low capturing ability of disulfides in SH2 reactions with moderately reactive carbon-centered radicals. The dichalcogenation reactions were carried out at 40−45 °C under neat conditions and upon irradiation with a tungsten lamp (500 W) of a mixture containing equimolar amounts of an alkene, diphenyl disulfide, and diphenyl diselenide. Under these reaction conditions, 1-(phenylthio)-2-(phenylseleno)-compounds could be obtained in moderate to high yields from both electron-rich and electron-poor alkenes, as illustrated by the examples depicted in Scheme 38, eqs a−c.205a The scope of this reaction has been extended to include 1,3dienes as unsaturated partners.205 The dichalcogenation of 1,3dienes was carried out in deuterated chloroform upon irradiation (hν > 300 nm) in the presence of an excess of diphenyl disulfide (2 equiv) and a substoichiometric amount (30 mol %) of diphenyl diselenide. The dichalcogenation products were obtained as 1,4-adducts, in agreement with the

The authors showed that the thioselenation product is the kinetic product of the reaction, but the latter undergoes homolytic cleavage of the allylic carbon−selenium bond upon irradiation and is converted into the dithiolation product in the presence of diphenyl disulfide. In agreement with these observations, the proposed mechanism involves the homolytic cleavage of the diselenide upon irradiation to form phenyl selenyl radical 68, which reacts with diphenyl disulfide to give PhSeSPh and phenylsulfanyl radical 69 (Scheme 40). Addition of thiyl radical 69 onto the terminal position of diene 70 furnishes allyl radical 71, which can be trapped by diphenyl diselenide to give 72 in a reversible trapping reaction, or alternatively with PhSeSPh by homolytic substitution at the sulfur or selenium atom. Homolytic substitution at sulfur is not Scheme 40

U


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reversible under these reaction conditions, and the resulting dithiolation product 73 accumulates in the reaction medium. 3.3.1.c. Oxidation with Molecular Oxygen: TOCO Process. The reaction of thiyl radicals with molecular oxygen has been the subject of intensive studies. As previously discussed in section 2.4.1, thiyl radical 74 reacts with molecular oxygen at diffusion controlled rates to form thiylperoxyl radical 75 (Scheme 41). However, the reverse reaction is also a very fast

The proposed mechanism involves the free-radical addition of thiyl radical 74, generated from the corresponding thiol by reaction with molecular oxygen onto the terminal position of the olefin. Following the mechanism depicted in Scheme 41 and in the absence of an electrophilic trap for the hydroperoxide resulting from the thiol−olefin cooxidation process (vide infra), rearrangement into the corresponding hydroxy sulfoxides 78 usually occurs spontaneously at room temperature.133,206,208 Following this work, the scope of the thiol− olefin cooxidation (TOCO) reaction has been extended to include electron-poor alkenes,209 as well as nonconjugated olefins208c and electron-rich alkenes such as vinyl sulfides122,210 and vinyl silanes (vide infra).211 The thiol−olefin cooxidation with simple terminal alkenes (used in ca. 2-fold excess) and aryl thiols has been reported to proceed efficiently upon irradiation with a black-light fluorescent lamp (Scheme 43, eq a).208c The

Scheme 41

Scheme 43

process, and this allows reactions involving the addition of thiyl radicals onto alkenes (or alkynes, see section 4.4.1.b) to be carried out under an atmosphere of air or oxygen. Under these conditions, carbon-centered radical 76 resulting from the addition process can be selectively trapped by oxygen to give peroxyl radical 77. The latter can evolve following different routes, including hydrogen atom abstraction from the thiol to give the corresponding hydroperoxide, and the addition onto a CC bond, usually in an intramolecular manner, to form a new carbon−oxygen bond. The thiol−olefin cooxidation (TOCO) process has been extensively studied since the pioneering work of Kharasch and co-workers in the early 1950s (vide infra),133 and this process, which consists formally of the addition of a thiol and molecular oxygen onto an alkene, has found elegant applications in organic synthesis. The peroxyl radical resulting from the trapping of a carbon-centered radical intermediate with molecular oxygen can engage in cascade reactions, thus leading to molecules presenting a endoperoxide core. Simple Addition. In the early 1950s, Kharasch and coworkers were the first to observe that “when equimolar quantities of styrene and propyl mercaptan (in heptane solution) are shaken at room temperature in an atmosphere of oxygen, very little, if any, of the usual free-radical addition product (PhCH2CH2S−n-Pr) is formed” and “the major product formed (89%) gives an elementary analysis corresponding to a combination of one molecule each of styrene, propyl mercaptan, and oxygen.”133 The structure of the product resulting from the thiol−olefin cooxidation with styrene and propanethiol was found to be α-hydroxy sulfoxide 78, which was isolated as a mixture of diastereoisomers (Scheme 42). Similar results were later obtained by Ford and co-workers with indene and thiophenol, with the oxidation taking place as with styrene at the benzylic position.206 The mechanism of this reaction has been the subject of intensive studies.207

course of the reaction depends strongly on the olefin and the choice of the solvent. This aspect is illustrated by the reaction between 1-pentene and p-toluenethiol, which failed to give the desired cooxidation product in pure n-hexane, while fair yields could be obtained in the presence of a cosolvent such as ethyl acetate or acetone. Moreover, in the case of olefins such as 1pentene 79, spontaneous rearrangement of the hydroperoxide 80 into the α-hydroxy sulfoxide 81 was not observed, and the later was obtained only after treatment with a catalytic amount of a vanadium- or molybdenum-based oxidizing agent (Scheme 43, eq b).208c Simple Addition Followed by Rearrangement. The hydroperoxides (or peroxyl radicals) resulting from the trapping with molecular oxygen can evolve prior to rearrangement into αhydroxy sulfoxides. For instance, using vinylsulfides in the thiol−olefin cooxidation reaction, α-thiocarbonyl compounds could be obtained directly. The addition of thiophenol onto substituted and terminal vinylsulfides was achieved under an atmosphere of oxygen, with or without electrochemical initiation.122,210 The reactions carried out under electrochemical initiation proved to be much faster, leading to αthioaldehydes and α-thioketones in high yields (Scheme 44, eqs a−c).122 High yields were also obtained for the reactions carried out in acetonitrile or acetic acid in the absence of electrochemical initiation. When the thiol R1SH used in this tandem reaction differs from the thiol R2SH that is released in the final step from the hydroperoxide (Scheme 44, eq b), then a mixture of α-thiocarbonyl compounds (with R1S or R2S) is

Scheme 42

V


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Scheme 44

Scheme 45

usually obtained. The required vinylsulfides can also be formed in situ from the corresponding alkynes (see section 4.4.1.b), thus allowing a direct conversion of alkynes into αthioaldehydes and α-thioketones.122 Likewise, the thiol−olefin cooxidation with ketene dithioacetals and thiophenol led to α(phenylthio) thiol esters, accompanied by the corresponding sulfoxides and/or α,β-unsaturated thioesters (Scheme 44, eq d).122 The thiol−olefin cooxidation with alkenyl acetate upon electrochemical initiation in Et4NOTs/AcOH proved to be less successful.210 Alkenyl silanes were found to participate in the thiol−olefin cooxidation, delivering α-thioaldehydes and α-thioketones in moderate to high yields, depending on the substitution at the vinyl silane moiety (Scheme 45, eq a).211 The regioselectivity of the addition of thiyl radicals onto vinylsilanes was found to be very sensitive to the presence of substituents at the β-position, and contrary to the case for the more reactive vinyl sulfides, only α-substituted vinylsilanes were found to react efficiently under these reaction conditions. A mechanism very similar to that with vinylsulfides has been proposed, however, with cleavage of a carbon−silicon bond as the final step (Scheme 45, eq b). An alternative rationale could involve rearrangement of the peroxyl radical intermediate by migration of the silicon atom onto the oxygen atom (Brook-type rearrangement), followed by fragmentation of the resulting carbon-centered radical with cleavage of the weak oxygen−oxygen bond (Scheme 45, eq c). This second mechanism would account for the exclusive formation of thiol ester 83 (and no traces of the corresponding acylsilane) from vinylsilane 82, which possesses both a silyl and a thiophenyl substituent on the same carbon atom (Scheme 45, eq d). The rearrangement of the hydroperoxides formed as the primary products of thiol−olefin cooxidation into the corresponding α-hydroxy sulfoxides can be suppressed by the trapping of the hydroperoxide by a carbonyl compound. For instance, the addition of thiophenol onto alkene 84 in acetic acid under an atmosphere of molecular oxygen gave

peroxyhemiketal 85 in good yield as a single diastereoisomer via the diastereoselective intramolecular addition of hydroperoxide intermediate 86 onto one of the two carbonyl groups (Scheme 46, eq a).212 Likewise, steroid 87 was successfully converted into 88, isolated as a mixture of diastereoisomers due to the lack of selectivity during the trapping of the carboncentered radical intermediate with molecular oxygen (Scheme 46, eq b).213 Cyclic peroxyhemiketals such as 88 were converted into 1,2dioxolanes 89 using a three-step sequence, which involves the Scheme 46

W


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the allyl alcohols (1,2-adducts) being obtained stereoselectively as the E- and Z-isomers, from E- and Z-1,3-pentadiene, respectively. This tends to indicate that, at relatively high concentrations in thiophenol, the allyl radical intermediates are trapped by molecular oxygen prior to isomerization and that under these conditions the reaction between the carboncentered radical and oxygen is not reversible, while at very low concentration in thiol the reversibility has been demonstrated (vide infra). Trapping of Peroxyl Radicals by CC Bonds. The presence of a second carbon−carbon double bond in the unsaturated partner allows intramolecular trapping of the peroxyl radical formed as an intermediate in the thiol−olefin cooxidation (TOCO) process. For the cyclization to be successful, one of the key features is that intramolecular addition of the peroxyl radical onto the CC bond must occur at such a rate that this process competes favorably with hydrogen atom abstraction from the thiol.221 Beckwith and coworkers showed that the thiol−olefin cooxidation process allowed the transformation of 1,4-dienes217 and 1,3,6trienes219a,b into 1,2-dioxolanes, albeit in moderate yields. For instance, the cyclic peroxide 91 could be obtained in 25% from 5-methylhexa-1,4-diene 90, by reaction with thiophenol (1 equiv) under an atmosphere of oxygen and in the presence of di-tert-butyl-peroxyoxalate (DTBPO) as a radical initiator (Scheme 49).217 The addition of the thiyl radical onto 90 takes place at the terminal position of the less hindered CC bond to give carbon-centered radical 92, which is rapidly trapped by molecular oxygen to give peroxyl radical 93. The latter undergoes 5-exo-trig cyclization, and, under these reaction conditions, the resulting carbon-centered radical 94 is trapped by molecular oxygen to form peroxyl radical 95. The latter then abstracts a hydrogen atom from the thiol to give hydroperoxide 96 and a thiyl radical, which propagates the chain. Hydroperoxide 96 is reduced in the presence of triphenyl phosphine to give the corresponding alcohol 91. The preference for the formation of cis-3,5-disubstituted 1,2-dioxolanes is in agreement with the Beckwith−Houk transition state model for 5-exo-trig cyclizations.219c,222 Similarly, the addition of thiophenol onto 5methylhepta-1,3,6-triene 97 under an atmosphere of oxygen led to 1,2-dioxolane 98, isolated in 49% as a single diastereoisomer after treatment with triphenyl phosphine, together with minor amounts of linear alcohols 99 and 100 (Scheme 49, eq b).219a,b This reaction is remarkable for a number of reasons. First, the addition of the thiyl radical occurs exclusively at the terminal position of the conjugated diene system and not at the terminal alkene, thus highlighting the higher reactivity of conjugated dienes as compared to isolated alkenes. Second, intermolecular trapping of the resulting allyl radical is reversible and regioselective under these reaction conditions. Because of the reversibility of the reaction between the allyl radical and molecular oxygen, both ratios 1,4/1,2-addition and 1,2dioxolane/linear alcohols strongly depend upon the initial concentration in thiol. Accordingly, the 1,2-dioxolanes were obtained in good yields only in highly diluted solutions. Finally, the 5-exo-trig cyclization occurs in a completely stereoselective manner, with only one of the two diastereomeric peroxyl radical intermediates (101) undergoing cyclization, while the other one (102) either leads to linear alcohol 99 or fragments back the allyl radical (Scheme 49, eq b).219a,b The reversible reaction of allyl radicals with molecular oxygen was also demonstrated for carotenoid-derived carbon-centered radical generated by

oxidation of the sulfur atom into the sulfone, followed by a radical β-fragmentation upon irradiation in the presence of (diacetoxyiodo)benzene (DAIB) and I2, and methylation of the carboxylic acid resulting from the rearrangement with diazomethane (Scheme 47).213 Scheme 47

Intermolecular trapping of the hydroperoxide intermediates with a carbonyl compound also proved to be feasible. For instance, the thiol−olefin cooxidation methodology applied to substituted allyl-,214 and homoallyl alcohols215 led to βhydroxy- and γ-hydroxy hydroperoxides, respectively. The latter could be condensed in situ with ketones in the presence of catalytic quantities of p-toluenesulfonic acid to give functionalized 1,2,4-trioxanes (Scheme 48). The 1,2,4-trioxane unit is the key pharmacophore of artemisinin, a highly active antimalarial agent. Scheme 48. Application to the Preparation of Functionalized 1,2,4-Trioxanes

The thiol−olefin cooxidation process has been applied to various polyunsaturated systems, including 1,3-dienes,216 1,4dienes,217 1,5-dienes,218 1,3,6-trienes,219 as well as conjugated enynes.208d,220 With some of these substrates, the CC bonds were found not to react independently (vide infra). Padwa and co-workers showed that conjugated enynes could be converted into β-sulfoxy acetylenic carbinol through the formation of a propargylic radical by regioselective addition of the phenylthiyl radical to the CC bond, and subsequent trapping of the carbon-centered radical with molecular oxygen. Rearrangement of the resulting hydroperoxide led to the corresponding hydroxysulfoxide, while treatment with triphenyl phosphine allowed the isolation of the sulfide.208d The thiol−olefin cooxidation of E- and Z-1,3-pentadiene with thiophenol under an atmosphere of oxygen proved to be moderately regioselective, the allyl radical intermediates reacting with oxygen to give preferentially the 1,4-adducts (1,4/1,2-adducts ≈ 2:1).216 This reaction was found to be highly diastereoselective, X


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Scheme 49

Scheme 50

addition of a thiyl radical to the conjugated polyene carotene.223 This process has been extended to include the more challenging 1,5-dienes, from which six-membered ring endoperoxides can be obtained. Bachi and co-workers applied the thiol−olefin cooxidation process to the total synthesis of antimalarial agent yingzhaosu A (Scheme 50) and its C14epimer,224 as well as the preparation of a series of active analogues,225 from readily available limonene 103. The overall process is extremely challenging in this case due to the particular structure of the diene, with the 6-exo-cyclization process being in competition with intermolecular hydrogen atom abstraction from the thiol, and also potentially with intramolecular hydrogen abstraction from the activated allylic position by the reactive oxygen-centered radical. As previously observed, addition of the thiyl radical takes place at the less hindered position, and due to the lack of stereocontrol during the trapping of the resulting carbon-centered radical, peroxyl

radical 105 is formed as a 1:1 mixture of diastereoisomers (Scheme 50). The latter undergoes 6-exo-trig cyclization to give carbon-centered radical 106. Unlike the initial trapping with molecular oxygen, the 2,3-dioxabicyclo[3.3.1]nonane system of 106 allows a highly diastereoselective reaction for the second trapping with molecular oxygen from the less hindered face to give 107. Alcohol 104 is then obtained following hydrogen abstraction from the thiol by peroxyl radical 107 and reduction of the resulting hydroperoxide with triphenylphosphine. The yields of endoperoxides remain relatively low (ca. 20−30%, calculated on the diene);225e however, considering the accessibility and the cost of the reactants (thiophenol, limonene, and oxygen), this approach represents a very attractive access to these structurally complex endoperoxides, some of which exhibit very promising activity for the treatment of malaria. 3.3.2. Intramolecular Trapping of the Carbon-Centered Radical. 3.3.2.a. Fragmentation Reaction: RingOpening of Vinyl Cyclopropanes. The carbon-centered radicals generated by addition of a thiyl radical onto the C C bond of vinylcypropanes have been shown to undergo cyclopropane ring-opening. The resulting radical species can then be trapped by hydrogen abstraction from the thiol. This fragmentation is a very fast process with rate constants in the range 108−109 s−1 (310 K) for most of the cyclopropylcarbinyl radicals,226 which allows for the fragmentation process to compete favorably with intermolecular reactions, as well as with most intramolecular processes. Alternatively, the carboncentered radical resulting from the β-fragmentation of the cyclopropylmethyl radical can engage further in carbon−carbon bond-forming processes. The allylsulfide moiety allows for the addition of radicals with concomitant release of a thiyl radical, and very elegant processes using only substoichiometric amounts of a source of thiyl radicals have been developed for the rearrangement of vinylcyclopropanes (see section 5.2.1.e). In particular, under nonreducing conditions and in the presence of an external olefin, efficient annulation reactions have been achieved, giving access to polycyclic compounds. The carboncentered radicals generated by the thiol-mediated ring-opening Y


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centered radical resulting from the fragmentation process reacts with triethylborane to form a boryl enamine 115 (Scheme 51, eq b).228 Depending on the reaction conditions, the latter can engage further in a radical oxygenation process, leading eventually to α-hydroxy oxime ether 113 after reduction of peroxyl radical 116 by the thiol (Scheme 51, eq b). Alternatively, 113 can react with aldehydes in an ionic aldol process to give β-hydroxy oxime ethers in a stereoselective manner, as illustrated by the preparation of 117 from 112 (Scheme 51, eq c). In the aforementioned reactions, the allylsulfide moieties generated upon addition of a thiyl radical onto the vinylcyclopropane unit remain intact at the end of the reaction. However, radical reactions taking advantage of the fragmentation of allyl sulfides upon addition of radical species are also well documented. Some examples of intermolecular additions, as well as cyclization and annulation processes, will be described in section 5.2.1.e. 3.3.2.b. Rearrangement and Cyclization of Nonconjugated Dienes. In the addition of thiyl radicals onto nonconjugated dienes, the CC bonds can either react independently or lead to rearrangements through intramolecular trapping of the carbon-centered radical generated in the initial addition step. In many cyclic dienes, addition occurs selectively at the more strained double bond, and products resulting from rearrangements are often observed. For example, the addition of thiophenol to 5-methylene-norbornene led to the exo addition products 118 and 119, together with tricyclic adduct 120. The latter results from the rearrangement of homoallyl radical intermediate 121 into cyclopropylcarbinyl radical 122 (Scheme 52).137e

of vinylcyclopropanes could also be trapped to form a new carbon−heteroatom bond. Here again, annulations taking advantage of the allylsulfide moiety have been developed (see section 5.2.1.e). Landais, Renaud, and co-workers used vinyl cyclopentenes such as 108, easily prepared by monocyclopropanation of silylcyclopentadienes, as radical acceptors for photogenerated thiyl radicals.227 The reversible addition of the thiyl radical onto the CC bond of 108 leads eventually to cyclopropylcarbinyl radical 110, which undergoes fragmentation to give carboncentered radical 111, stabilized by the neighboring ester group. Hydrogen atom abstraction from the thiol then furnishes cyclopentene 109 and regenerates a thiyl radical that propagates the chain (Scheme 51, eq a).227 The addition of Scheme 51

Scheme 52

Similar rearrangements have been observed in norbornadiene derivatives137b where substitution at C-7 can influence facial selectivity,137d,g,229 while substitution of the methylene bridge in 7,7-dimethylnorbornene proved to have no effect in directing the addition of thiophenol.137f The formation of cyclopropylcarbinyl radical intermediates in norbornadiene derivatives can also lead to other skeletal rearrangements, as illustrated by the addition of thiophenol to hexachloronorbornadiene 123, which results in the formation of 125, beside the expected 1:1 addition product 124 (Scheme 53, eq a).230 Following addition of the thiyl radical, presumably from the less hindered endo-face, and subsequent 3-exo-trig cyclization onto the neighboring CC bond, cyclopropylcarbinyl radical 126 undergoes fragmentation to give the more stable α-chlorosub-

the thiyl radical at the β-carbon center takes place in a highly stereoselective manner, opposite to the bulky silyl group. The fate of the stabilized carbon-centered radical resulting from the fragmentation process depends upon the reaction conditions. For instance, Naito and co-workers reported the use of vinylcylopropyl oxime ethers such as 112 in domino reactions promoted by a thiol or a disulfide in the presence of triethylborane. The ring-opening of the cyclopropyl moiety is initiated by addition of a thiyl radical onto the terminal position of vinylcyclopropyl oxime ether 112. The stabilized carbonZ


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Scheme 53

Scheme 54

double bond, thus allowing the preparation of terpene-based monomers, which were used for the preparation of renewable polymers (Scheme 55).233 Scheme 55

On the contrary, 1,6-dienes generally lead to cyclized compounds through initial addition to the more reactive double bond, followed by a 5-exo-cyclization process. For example, the Kuehne group reported in the 1970s the addition of dimethylsulfide onto α-acoradiene 131 in a highly regioselective manner to give tricyclic compound 132 (Scheme 56). In this case, the addition of a methyl thiyl radical, generated from the disulfide upon photochemical activation, takes place exclusively at the more reactive exocyclic double bond. The resulting carbon-centered radical intermediate 133 then undergoes a 5-exo cyclization and eventually gives 132.234

stituted carbon-centered radical 127. The latter then abstracts a hydrogen atom from the thiol to give 125 (relative configuration not established) and a thiyl radical, which goes on to propagate the chain. Similar rearrangement was observed in the addition of t-BuSH onto 1,2,3,4,7,7hexamethylbicyclo[2.2.1]heptadiene.229 Likewise, Hodgson and co-workers have observed complete skeletal rearrangements in the addition of thiophenol to 7-azabicyclo[2.2.1]heptadienes such as 128 (Scheme 53, eq b).231 Transannular cyclizations have also been reported with 1,5dienes, as illustrated by the cyclization of germacra1(10),4,6(11)-triene 130 upon irradiation in the presence of thiophenol or diphenyl disulfide (Scheme 54).232 In compounds containing two or more isolated double bonds, the addition of the thiyl radical is not necessarily followed by a rearrangement. For instance, selective monoaddition of a thiol at the more reactive exocyclic double bond of the 1,5-diene (S)-(−)-limonene 103 was achieved in the absence of initiator and under vacuum (P = 200 mbar) to exclude oxygen from the medium. Sequential addition of a second thiol then occurred at the less reactive endocyclic

Scheme 56

AA


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Dialkyl diallylmalonates are the ideal substrates for thiolmediated cascade reactions. Cyclopentane derivatives are usually obtained in high yields as a mixture of cis and trans isomers. In the absence of steric constraints such as 1,3-allylic strain, these cyclizations usually proceed with moderate levels of stereoselectivity.234 Kuehne and co-workers reported in the 1970s the first examples of thiyl radical-mediated cyclization of 1,6-dienes.234 Interestingly, the radical addition of EtSH onto diallyl diethylmalonate in solution in benzene gave the desired cyclic product in 92% yield upon initiation by photolysis of diphenyldisulfide, while the reaction carried out with EtSH alone with benzoyl peroxide as a radical initiator led to >90% recovery of starting material (Scheme 57).234 The addition of

Scheme 58

Scheme 57

dimethyldisulfide upon photochemical activation led to a mixture of methanethiol and dimethyl disulfide adducts (vide supra).234 The thiol-mediated cyclization of 1,6-dienes was also reported to proceed on solid support. However, so far the use of this approach is hampered by the need for large excesses of thiol and radical initiator.235 As previously discussed, the addition of a thiyl radical to nonsymmetrical dienes takes place at the more reactive CC bond. For instance, Barrero and co-workers reported a short total synthesis of (±)-dehydroiridomyrmecin 135 from linalyl acetate 134, which is based upon the formation of the fivemembered ring through a thiol-mediated cyclization (Scheme 58).236 In their approach, the addition of the thiyl radical takes place at the less substituted CC bond of 134, and following 5-exo-trig cyclization and hydrogen atom abstraction from the thiol, cyclopentane derivatives 135 were obtained as a mixture of diastereoisomers. Both the nature of the substituents on the second CC bond and the choice of the thiol proved to be crucial for the success of this radical cascade. For instance, the addition of alkanethiols to 134, which possesses a second electron-rich CC bond, proved to be far more efficient than the addition of thiophenol. In the case of thiophenol, the cyclization onto an electron-rich alkene does not compete efficiently with the reverse reaction (Scheme 58, eq a).236 The cyclization onto a conjugated alkenyl moiety proved to be easier, and it allowed the formation of the desired cyclopentane 137 in high yields, even with thiophenol (Scheme 58, eq b).236 In their formal synthesis of aplysin, Harrowven and co-workers used the higher reactivity of the electron-rich CC bond of enol ether 138 to differentiate between the two terminal double bonds in the cyclization leading to 139 (Scheme 58, eq c).237 The source of hydrogen atom in this reaction is presumably the solvent, although hydrogen atom abstraction from the benzylic position in 138 and/or 139 cannot be ruled out. With more flexible 1,6-dienes, the course of the reaction with dialkyl disulfides differs from the previous example by the stereoselectivity in the cyclization process, which favors this time the cis-isomer, as expected for a 5-exo-trig cyclization of this type.222 The carbon-centered radical resulting from the cyclization is then in an appropriate position to undergo homolytic substitution (SH2) at the sulfur atom,180 thus leading

to thiabicyclo[3.3.0] skeletons with release of an alkyl radical.238 The addition of tert-butyl sulfanyl radical onto 1,6dienes could be achieved upon irradiation by using the corresponding disulfide as the source of thiyl radicals. The use of quartz photochemical cells usually gave the best results, but Harrowven and co-workers demonstrated the positive effect of triethylborane in the reactions carried out in pyrex photochemical cells (Scheme 59, eq a).238a Landais and coworkers extended this methodology to include 1,6-dienes presenting an allylsilane moiety, which were found to undergo highly regio- and stereoselective cyclizations upon irradiation in the presence of di-tert-butyldisulfide (Scheme 59, eqs b,c).238b Diallylamines behave similarly, affording polysubstituted pyrrolidines in high yields,239 provided that an electronwithdrawing group is present on the nitrogen atom to prevent competitive hydrogen abstraction from the allylic position (see section 8.1.2). For instance, the cyclization of diallylamine 140 could be achieved in water, in the presence of thiophenol and a water-soluble radical initiator such as 2,2′-azobis(2methylpropionamidine)dihydrochloride (V-50) (Scheme 60, eq a).239b Likewise, free-radical addition of thiols onto diallyl ethers afforded tetrahydrofurans (Scheme 60, eq b).239b AB


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Scheme 59

at the terminal position of the more electron-rich CC bond of 141, and the resulting carbon-centered radical undergoes regioselective cyclization in a 5-exo-trig manner, thus delivering the corresponding five-membered ring heterocycle.241 The regioselectivity, however, is strongly dependent upon the substitution at the two CC bond, and a complete reversal in the regioselectivity could be observed in some cases, as illustrated by the cyclization of 142 (Scheme 61, eq b).241 The methodology also applies to the analogous enynes;242 however, in this case, the addition occurs preferentially at the more reactive alkynyl moiety, and these will be treated separately (see section 4.4.2.a). The additions of thiyl radicals onto 1,6-dienyl systems in which one of the two CC bonds is part of an allylsulfide moiety are very efficient processes, and, in this case, catalytic versions with respect to thiol have been developed (see section 5.2.1.d).239a,240,243 3.3.2.c. Ketones, Oximes, and Hydrazones as Intramolecular Radical Traps for Alkyl Radicals. Although not well documented, the intramolecular trapping of carboncentered radicals resulting from the addition of a thiyl radical onto an alkene by a CO bond is feasible. This is illustrated by the addition of thiyl radicals to norbor-2-en-5-one 143 from which rearranged products 146 were obtained, together with products 144 and 145 resulting from simple addition onto the CC bond (Scheme 62).244 Interestingly, the proportion of

Scheme 60

Scheme 62

In the aforementioned examples of cyclizations of 1,6-dienes, stereoelectronic factors favored the formation of the 5-exo-trig cyclization products. This is also the case for amides,240 and related compounds such as O-alkyl-hydroximates, 141, which allow an indirect access to γ-lactones, while the corresponding esters fail to cyclize (Scheme 61, eq a).241 The addition of electrophilic thiyl radicals takes place in a regioselective manner Scheme 61

the different products was found to depend on the nature of the thiol used but surprisingly not on the dilution conditions. A mechanism very similar to that proposed in the previous section for the rearrangement of norbornadiene derivatives accounts for the formation of 146. The addition of carbon-centered radicals onto CN acceptors is a very fast process, and in many cases cyclizations have been reported with rate constants higher than those for the related cyclizations onto CC bonds.245 As a result, the trapping of alkyl radicals resulting from a thiol−ene coupling onto carbon−nitrogen double bond has been more successful than the corresponding additions onto ketones. El Kaim and Naito reported independently the addition of thiophenol onto AC


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hydrazones and oximes having a terminal alkenyl moiety.246 El Kaim and co-workers reported the cyclization of oximes and hydrazones. Five-membered rings could be obtained in high yields in refluxing cyclohexane in the presence of AIBN as a radical initiator (Scheme 63, eq a).246a For six-membered rings,

Scheme 64

Scheme 63

the cyclization does not compete favorably with the intermolecular hydrogen abstraction from the chain-carrier reagent.246a,247 On the other hand, successful 6-exo-cyclizations involving the more reactive alkenyl radicals have been described (see section 4.4.2.b). Naito and co-workers extended the scope of this reaction to include the cyclization of diallyl ethers246b and α,β-unsaturated hydroxamates such as 150 (Scheme 63, eq b)248 and showed that these reactions could be carried out in water or in a MeOH/H2O mixture by using water-soluble 2,2′azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride (VA044) as a radical initiator.247 Friestad and co-workers have developed an elegant approach to chiral amino alcohols based upon a thiyl-mediated cyclization of α-hydroxy hydrazones in which the alkenyl side chain is linked via a silyl ether. Following addition of the thiyl radical and cyclization of the resulting carbon-centered radical onto the hydrazone moiety, treatment with potassium fluoride allowed the ring-opening of the cyclic silyl ether to give the corresponding allylamines. This two-step sequence gave 1,2amino alcohols in good overall yields and high levels of diastereoselectivity (Scheme 64, eq a).249 The related 6-exocyclizations proved to be more difficult to achieve, with the hydrogen abstraction from the thiol by the carbon-centered radical intermediate competing with the desired cyclization. However, in conformationally constrained systems, successful 6-exo-cyclizations have been reported. Depending on the relative configurations of the precursors, excellent levels of stereocontrol can be attained (Scheme 64, eq b).250 The observed diastereoselectivity was explained by a chairlike transition state in which the hydrazone moiety adopts a contra-intuitive pseudoaxial disposition to minimize vicinal dipole repulsions with the C−O bond. 3.3.2.d. Epoxidation of Allylperoxides. The radical addition of methyl thioglycolate to allylic peroxides was found to give epoxides. In this reaction, the carbon-centered radical intermediate resulting from the addition process reacts with the peroxide moiety to give the corresponding epoxide via a SHi mechanism (Scheme 65).251

Scheme 65

an independent treatment. Given that radical addition to olefin usually affords the most stable radical, it might be expected that attack at the central sp-carbon atom of allenes would be favored as this would form a resonance-stabilized allylic radical, whereas attack at the terminal carbon would furnish a reactive vinylic radical. However, radical 155 resulting from attack of the central carbon of allene 151 resembles a primary radical in the transition state rather than an allylic one as the unpaired electron does not overlap with the π-orbital of the remaining double bond (Scheme 66).174b,252 As a result, the free-radical addition of thiols onto the simple allene 151 generally leads to a mixture of allyl sulfide 152 and isopropenyl sulfide 154.253 A 90° rotation allows nonallylic radical 155 to interconvert rapidly into the more stable allylic radical 156, which cannot undergo β-fragmentation, thus rendering the addition of thiyl radical at the central carbon atom practically nonreversible,102,252b although this aspect has been debated. Addition of thiyl radicals onto allenes was studied by a number of research groups in the early 1960s.174b,252−254 Reaction of ethanethiol with allene led preferentialy to allyl sulfide 158 arising through attack at the terminal carbon atoms, while vinyl sulfide 157 resulting from the addition at the

3.4. Addition of Thiyl Radicals to Allenes

3.4.1. Intermolecular Addition to Allenes: Regioselectivity. Allenes represent a special class of olefins deserving AD


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Pasto and co-workers for the addition of thiophenol onto alkylsubstituted allenes such as 160, albeit with a higher regioselectivity (Scheme 67, eq b).102 Deuterium-labeling experiments demonstrated that hydrogen abstraction from the allylic position in vinyl sulfides by the thiyl radical took place under these reaction conditions.102 Contrary to allene and monoalkyl allenes, 1-phenyl-allenes (Scheme 68, eq a)255 and 1,1-dialkyl allenes102,174b,256 such as

Scheme 66

Scheme 68. Regioselective Addition onto 1-Phenyl-allene and 3-Methyl-1,2-butadiene

internal position was rapidly converted into 1,3-diethylthiopropane 159 upon addition of a second molecule of ethanethiol (Scheme 67, eq a).174b,252a The regioselectivity of the initial

3-methyl-1,2-butadiene 162 (Scheme 68, eq b)174b react exclusively at the central sp-carbon atom and afford the corresponding vinyl sulfides. The exclusive attack upon the internal carbon atom of 162 can be explained by the increasing stability of the radical intermediate upon attack at the central carbon atom with increasing substitution of the allene. Kinetic isotope effects of the reaction between the benzenethiyl radical and alkyl-substituted allenes have also been investigated.102,256 This led to the proposal of a very early transition state in which little rotation of the orthogonal groups at the termini of the allene has occurred. The relative reactivities and chemoselectivities are governed by early frontier molecular orbital interactions between the SOMO of the benzenethiyl radical and the occupied π- molecular orbitals (HOMO) of the allene. On the contrary, experimental and theoretical studies reported by Pasto and L’Hermine support a thermodynamic control for the addition of thiophenol to heterosubstituted allenes, including phenylallene 161, methoxyallene 163 (Scheme 69, eq a), carbomethoxyallene, cyanoallene, chloroallene 164 (Scheme 69, eq b), and (phenylthio)allene.255b With all of these heterosubstituted allenes, the addition of the phenylthiyl radical takes place selectively at the central carbon atom, thus giving the corresponding vinyl sulfides as a mixture of E- and Z-isomers as the main products. In the case of chloroallene 164, the

Scheme 67

attack proved to depend upon both the nature of the thiol and the temperature.252a Upon irradiation with UV-light, 1,3diaddition products were obtained selectively from allene with various thiols, including aliphatic thiols, dialkyldithiophosphoric acids, thiolacetic acid, and mercaptoacetic acid.254b Because of the high propensity of allyl phenyl sulfide to undergo β-fragmentation upon addition of radical species, diadditions leading to 1,3-disubstituted mercaptopropanes are more difficult to achieve in high yields with aromatic thiols such as thiophenol.254b The addition of thiols onto alkyl-substituted allenes has been studied in detail.102,174b In this case, however, the lack of regio- and stereoselectivity strongly limits the utility of this reaction for synthetic purpose. For instance, attack of ethanethiyl radicals upon 1,2-butadiene occurs at all three positions, thus resulting in a complex mixture composed of the different regio- and (E/Z)-stereoisomers, together with bisaddition products.174b Similar results have been obtained by

Scheme 69

AE


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products distribution was complicated by the formation of products resulting from the substitution of the chlorine atom by the thiol via a radical addition−fragmentation mechanism.255b However, upon irradiation with a 400 W high-pressure mercury lamp at 20 °C and in the presence of propylene oxide to scavenge the hydrogen chloride liberated during the reaction, 1,2-dithiopropene 165 could be obtained in high yields, with only minor amounts of allylsulfide 166 resulting from the mono addition at the terminal position (Scheme 69, eq b).257 Endo and co-workers have extensively studied the use of alkoxyallenes in radical polymerization. Phenoxy- and methoxyallenes were polymerized in the presence of various radical initiators.258 In the presence of dithiols such as 1,4benzenedithiol 167 or bis(4-mercaptophenyl)sulfide, diphenoxy- or dialkoxyallenes such as 1,4-bis(allenoxy)xylylene 168 (Scheme 70) or 1,4-bis(allenoxy)benzene underwent polymer-

Scheme 71

of a mixture of (PhS)2 and (PhTe)2 through filters with a tungsten lamp (hν > 400 nm) at 40 °C leads to the formation of PhSTePh via the initial cleavage of the tellurium−tellurium bond (Scheme 72). Photolytic cleavage of the sulfur−tellurium Scheme 72

Scheme 70

bond in PhSTePh generates both PhS• and PhTe•. The addition of the benzenesulfanyl radical takes place regioselectively at the central carbon atom, and the resulting allyl radical 170 is then trapped by PhSTePh to give dithiolation product 169 as a mixture of E- and Z-isomers, and PhTe• that dimerizes to regenerate (PhTe)2 or, alternatively, react with (PhS)2 to form PhSTePh and PhS•. 3.5. Miscellaneous

In strained systems, thiols can add directly to cyclopropyl ring systems leading to the ring-opened products. This was first observed by Szeimies and co-workers who noted that thiols can add to the tetracyclo[5.1.0.0.0]octane ring system and to [1.1.1]propellane, to give tricyclo[4.2.0.0]octane and bicyclo[1.1.1]pentane derivatives, respectively (Scheme 73).262 Diphenyl disulfide was also found to add onto strained propellane ring systems.263,264

259

or alternatively upon ization. In the presence of AIBN, irradiation,260 high molecular weight polymers were obtained with reactive electron-rich allenes. Further modifications such as the formation of cross-linked polymers via cationic polymerization have been reported.259a The photochemically initiated polymerization of dithiols with chloroallene gives polymers containing the 1,2-dithiopropene units.257 3.4.2. Intermolecular Trapping: Dichalcogenation. Dichalcogenation of allenes could be achieved upon irradiation (hν > 300 nm) in the presence of a binary system composed of equimolar amounts of diphenyldisulfide and diphenyl diselenide. Contrary to alkenes, which undergo dichalcogenation under these reaction conditions to furnish 1-(phenylthio)-2(phenylseleno)-alkanes through the initial addition of phenyl sulfanyl radical followed by intermolecular trapping (see section 3.3.1.b), allenes react first with a phenylselenyl radical to give the kinetic diselenation products. The latter present an allylselenyl moiety, which is cleaved under the photochemical conditions, thus allowing the thermodynamic thioselenation product to accumulate.261 The direct introduction of two sulfanyl moieties onto allenes using diphenyl disulfide proved to be unsuccessful, while the use of a (PhS)2/(PhTe)2 binary system allowed the dithiolation products 169 to be obtained in moderate to good yields (Scheme 71).261 In this case, the reaction proceeds differently from that for the thioselenation, with the addition of a thiyl radical at the central carbon atom taking place as the initial step. Irradiation

Scheme 73

4. ADDITION OF THIOLS TO ALKYNES AND RELATED CARBON−CARBON TRIPLE BONDS Thiols add efficiently onto the carbon−carbon triple bond of alkynes under radical conditions. The process delivers vinylsulfides, which can easily be transformed into useful functional groups. Both internal and terminal alkynes have been found to AF


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phenylacetylene led preferentially to the Z-vinyl sulfide. Isomerization of the Z-adduct could be achieved in the presence of thiophenol under heating or irradiation, whereas alkyl thiols (except thiolacetic acid) proved to be ineffective. This isomerization is the result of a reversible addition of a thiyl radical to the vinyl sulfide without formation of significant amount of diadduct. Accordingly, by carrying out the reaction in the presence of a large excess of alkyne, the isomerization could be suppressed, and a higher selectivity in favor of the Zisomer was observed (Z/E > 84:16).265c These observations were later confirmed by Montevecchi and co-workers for both terminal and internal alkynes (see section 2.3.4).99 As illustrated in the addition of sterically hindered mesitylenethiol to mesitylacetylene, which also gave the Z-isomer predominantly, the presence of large substituents on the alkyne and/or on the sulfur atom is not sufficient to reverse the selectivity.266 Similarly, the addition of thiolacetic acid to 1-hexyne carried out at 0 °C in the absence of any radical initiator led preferentially to the Z-isomer. A constant isomeric ratio (Z/E = 82:18) was observed when the reaction was performed in the presence of a 6-fold excess of alkyne. With lower 1-hexyne/ thiolacetic acid ratios, the isomeric composition was dependent on both the extent of the reaction and the alkyne/thiol ratio.267 The formation of thiyl radicals from thiols can also be achieved in the presence of transition metal complexes. For instance, the addition of alkyl- and aryl thiols to phenylacetylene could be achieved in high yields in the presence of substoichiometric amounts of manganese(III) salts. The more stable E-isomer could be selectively obtained by using a slight excess of thiol, probably as the result of the reversible addition of the thiyl radical onto the vinylsulfide (Scheme 75). In some

participate in this reaction, as well as electron-rich ynamides and ynoates. As compared to the corresponding alkyl radicals, the high reactivity of the alkenyl radical resulting from the addition process onto a carbon−carbon triple bond allows for a wider range of inter- and intramolecular trapping reactions (radical cascades), which will be discussed in this section.6b 4.1. Simple Addition to Alkynes

4.1.1. General Trends. The early examples of radical additions of aromatic thiols to phenylacetylene have been reported to proceed efficiently, even in the absence of radical initiator.265 Nevertheless, the addition of aryl thiols to phenylacetylene could be accelerated by carrying out the reaction in the presence of various sources of radical species such as peroxides and AIBN, or upon irradiation with UVlight.266 On the other hand, the addition of alkyl thiols to phenylacetylene is a very slow reaction at room temperature in the absence of radical initiator. Heating the reaction mixture dramatically increases the rate of addition. Peroxides or UVlight irradiation are also efficient in promoting the reaction of alkyl thiols to phenylacetylene.265c The proposed mechanism for the addition of thiyl radicals to alkynes is as follows: (a) the addition of a thiyl radical to terminal alkynes occurs regioselectively at the less hindered position and gives a vinyl radical intermediate as a E/Z-mixture of isomers in equilibrium; (b) hydrogen atom abstraction from the thiol by the resulting vinyl radical leads to the E- and Zvinyl sulfides; and (c) eventually, the reversible addition of a thiyl radical to the vinyl sulfide may promote the isomerization of the kinetically favored Z-isomer into the thermodynamically more stable E-vinyl sulfide (Scheme 74). If the β-sulfanyl alkyl Scheme 74

Scheme 75

cases, thiocetals could be isolated as the major side product. The formation of thioacetals could be explained by addition of a thiyl radical to the vinyl sulfide and subsequent oxidation of the resulting radical by Mn(III) to give a carbocation, which could be trapped by water.20 Trialkylboranes have also been utilized as radical initiators to generate thiyl radicals.268 Oshima and co-workers have developed an efficient addition of arene- and alkanethiols to terminal alkynes using commercial solutions of Et3B in hexane to promote the reaction at room temperature.268a Good to high yields (70−91%) were obtained using only 1.1 equiv of PhSH and a stoichiometric quantity of initiator (Scheme 76, eq a). The reaction could not reach completion with only substoichiometric amounts of Et3B. Different solvents (such as benzene, toluene, CH2Cl2, or THF) were suitable for this addition reaction, but no reaction occurred in hexane. The reaction conditions were optimized for the addition of less reactive alkanethiols. In this case, the presence of MeOH (4 equiv) was required to obtain high yields and fast conversions (Scheme 76, eqs b,c). Because alkanethiyl radicals react much faster with primary trialkylboranes than with terminal alkenes,84b,269 the dramatic effect of MeOH on the reaction

radical resulting from the addition onto the vinyl sulfide can be trapped prior to the β-fragmentation, the bis-addition product is obtained. The addition of two molecules of thiol onto an alkyne has found many applications as a tool for “click” chemistry (see section 4.2). The stereoselectivity of the radical addition of thiols to alkynes has been studied for a long time. Oswald and coworkers observed that the addition of alkyl- and aryl thiols to AG


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4.1.2. Synthetic Applications. The addition of benzenethiol to terminal alkynes proved to be very efficient for the formation of vinylsulfides. For instance, the AIBN-initiated addition of thiophenol to the terminal alkyne of ynoic acid 171 provided the corresponding vinylsulfide 172 (88% yield), which was used as intermediate in the synthesis of cyclohexanone derivatives (Scheme 78). The reaction was carried out in

Scheme 76

Scheme 78

outcome may be due to the regeneration of the thiol by methanolysis of Et2B(SR)270 that is formed upon SH2 reaction at the boron atom (see section 2.4.5). Disulfides generally lead to either bis-mercapto adducts or benzothiophene derivatives when engaged in reactions with alkynes. Some rare examples of vinylsulfide formation using diphenyldisulfide have nevertheless been disclosed. Ishibashi and co-workers reported the addition of the phenylthiyl radical (generated from the corresponding disulfide) onto terminal and disusbtituted alkynes, in the presence of a large excess (typically 40 equiv) of a tri-n-propylamine (Scheme 77).271 The

refluxing benzene solution of alkyne and thiophenol (2-fold excess). Under these highly concentrated conditions, no cyclized products resulting from the rearrangement of the vinyl radical intermediate via a 1,5-hydrogen transfer [see section 4.4.2.e] were observed.273 The addition of thiophenol to enyne 173 delivered the chiral diene 174, a key intermediate in the total synthesis of (+)-compactin. Diene 174 was obtained in excellent yield but with a moderate E/Z selectivity. Gratifyingly, the Z-vinyl sulfide was converted into the E-isomer under the thermal conditions of the subsequent Diels−Alder reaction (Scheme 79).274

Scheme 77

Scheme 79

Although the addition of a second molecule of thiol onto the vinylsulfide intermediates has been shown to be about 3 times faster than the initial addition onto the alkyne (vide infra),275 examples of polymerizations leading to poly(vinylene sulfide)s have also been reported. For instance, Tang and co-workers achieved the copolymerization of aromatic diynes and dithiols in the presence of rhodium(I) catalysts. The high molecular weight linear vinylene polymers such as 175 were obtained in high yields and with up to 100% E-selectivities, depending on both the nature of the monomers and the rhodium catalyst (Scheme 80).276 4.2. Bis-Addition of Thiols to Alkynes: The “Thiol−Yne” Reaction

The addition of thiols to propargyl alcohols277 and acetylene278 was described in the 1950s.277 The resulting vinylsulfides have been utilized as precursors to unsaturated aldehydes. The transformation could be achieved via acid-catalyzed hydrolysis followed by allylic transposition. However, this approach is of only little synthetic utility for the preparation of α,βunsaturated aldehydes.279 For example, upon irradiation with UV-light the reaction of stoichiometric amounts of ethanethiol and propargyl alcohol gave mainly the bis-adduct.279a The αsulfanyl radicals resulting from the bis-addition of alkyl thiols onto propargyl alcohol have been observed by ESR spectroscopy.280 Kinetics indicate that the addition of a thiyl radical onto a vinylsulfide is indeed very rapid (about 3 times faster than the addition onto the starting alkyne).275 The bis-addition of thiols to alkynes proved to be an efficient method to form

authors proposed a spontaneous single electron transfer (SET) from the tertiary amine to the diphenyldisulfide, a process generating, besides the thiyl radical, a thiolate anion and the radical cation of the tertiary amine. Acid−base reaction between the thiolate anion and the radical cation would give an αaminoalkyl radical and thiophenol, which could then act as a hydrogen atom donor to trap the vinyl radical intermediate. On the other hand, one could envisage a direct hydrogen atom transfer from the tertiary amine to the highly reactive vinyl radical. The resulting α-aminoalkyl radical is a good oneelectron donor,272 and SET to the diphenyldisulfide would generate the iminium ion and a thiyl radical, which could sustain the radical chain. AH


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choice to achieve the linkage, the reverse approach, which implies the addition of a thiol-terminated polymer onto an alkyne, also proved to be a viable approach for the synthesis of multiarmed biodegradable copolymers.286 The properties of polymers and surfaces can be easily tuned by introducing new functionalities via a thioether linkage. Biodegradable polymers, such as polyphosphoesters,287 poly(ε-caprolactone),288 or polypeptides,289 have been modified using this approach. Thiols presenting carboxylic acid moieties have been successfully incorporated into polymer chains.290 Because the presence of dicarboxylic groups allows for metals to coordinate, using the “thiol−yne” approach for surface postfunctionalization, efforts have been made to develop drug delivery carriers, such as for cis-diaminediaquaplatinum(II) dication (cisplatine). Dendrimers,291 as well as functionalized surfaces of statistical copolymers,292 micelles,292 cross-linked micelles,292 and polymeric nanoparticles,293 have been synthesized for this purpose. Strategies to access multifunctional polymer brush surfaces have also been reported,294 as well as the functionalization of surfaces using microcontact chemistry (reactive microcontact printing).295 Polybenzylglutamate has been coupled with dodecanethiol to obtain an amiphiphilic block copolymer that could be used to form a polypeptide-based polymersome.296 Sugar-derived thiols have been linked to microporous polypropylene membrane297 and polymer-coated quartz surfaces.298 Contrary to the related “thiol−ene” reaction, which leads to a linear linkage between the thiol and the alkene counterpart, the bis-addition of thiols to alkynes gives a branched linkage by nature (Scheme 82). Highly branched polymers, such as dendrimers291,299 and hyperbranched polymers,275,300 have been synthesized using the bis-addition of thiols to alkynes. For instance, Stenzel and co-workers reported the preparation of a highly functionalized dendrimer (48 end-group functionalities) in only three steps from 177 (Scheme 83).291 The use of 1-thioglycerol 178 allows the chain elongation with the introduction of four hydroxyl groups per alkyne. Each of the thiol−yne reactions were carried out under UV-light irradiation in the presence of a sensitizer (typically 2,2-dimethoxy-2-phenyl-acetophenone (DMPA)) and was complete within 10 min. Syntheses of dendrimers299a and polymers300c,301 taking advantage of the nucleophilic properties of thiols, thus combining nucleophilic “thiol-click” chemistry5c and radical “thiol−yne” reactions, have been reported. Hyperbranched polymers offer the advantage over the welldefined dendrimers of being accessible in a single step. Hyperbranched polymers have been obtained via the copolymerization of tetrafunctional thiols with dialkynes,275 as well as via a sequential “click” approach combining nucleophilic “thiol−ene” and radical-mediated “thiol−yne” reactions with propargyl acrylate and dithiols.300c This approach also proved successful for the preparation of linear polymers.302 Alternatively, the two required functional groups could also be located on the same molecule. Perrier and co-workers reported that hyperbranched polymers could be obtained from both small molecules, such as prop-2-ynyl-3-mercaptopropanoate,300a,303 or macromolecules of this type.300a,b The first approach using prop-2-ynyl-3-mercaptopropanoate has given access to a hyperbranched polymer in which the terminal alkynes could then be used to introduce further functionalities, such as metal complexes via, for instance, C−H activation.303 More recently, this approach has been used to polymerize

Scheme 80

macrocycles. For instance, the trialkylborane-initiated addition of alkyl thiol has also been utilized in macrocyclizations of 1,8and 1,9-dithiols derived from 1,3- and 1,3-diols and mercaptoacetic acid with terminal alkynes. Low to moderate yields (15− 48%) of the resulting 12- and 13-membered sulfur-containing lactones have been obtained (Scheme 81, eq a).268d,e High yields have been obtained for the formation of large-sized rings, such as the 30-membered ring system of rotaxane 176, using a secondary dialkylammonium ion as a template. The bisaddition was carried out under UV-light irradiation (365 nm) in the presence of substoichiometric amounts of 2,2-dimethoxy2-phenylacetophenone as the initiator (Scheme 81, eq b).281 The bis-addition of alkyl thiols has recently found new applications in different fields of material science as a tool for “click” chemistry. Different approaches can be envisaged to access functionalized materials using the “thiol−yne” reaction. For instance, highly branched polymers can be synthesized using the radical polymerization of alkynes and thiols. The postfunctionalization of polymers and the modification of surfaces can be achieved thanks to the addition of thiols onto alkynyl side chains. Similarly, the derivatization of peptides and polypeptides can be achieved under mild conditions. The use of UV-light irradiation in the presence of a sensitizer is a very common way to initiate these coupling reactions. The addition of thiols to alkynes under radical conditions as a new tool for “click” chemistry in material science is very recent, and it was recognized as a very useful and promising method immediately after the first reports appeared.5c,282 For instance, the radical-mediated “thiol−yne” reaction proved to be a viable approach to achieve postfunctionalization of polymers283 and nanoparticles,284 as well as for the modification of surfaces. This approach is particularly attractive because it allows the introduction of sensitive functional groups onto the surface without using expensive and/or sensitive monomers during the elaboration of the polymer itself. Reactive polymer coatings prepared via chemical vapor deposition (CVD) polymerization have been coupled with thiols under photochemical initiation.163 Similarly, synthetic diamond films produced via CVD-polymerization have been funtionalized with various thiols, including 1H,1H,2H,2Hperfluorodecanethiol, 6-(ferrocenyl)-hexanethiol, and thiolated oligonucleotide.285 Although the coupling between a yneterminated polymer and a thiol appeared as the method of AI


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Scheme 81

link density to be obtained, resulting in higher glass transition temperatures (TgS).305 The incorporation of hyperbranched oligomers into resins has also been shown to reduce both shrinkage and shrinkage stress.301c Microfluidics technology has been used to produce thiol- and yne-functionalized monodisperse macroporous and nonporous beads.306 Peptides have been modified thanks to the “thiol−yne” approach. Dondoni and co-workers have achieved the conjugation of glycosyl thiols with S-propargyl cysteinecontaining peptides.307 Interestingly, when the addition onto the alkyne was carried out under UV-light irradiation with 10 mol % of 2,2-dimethoxy-2-phenylacetophenone (DMPA) as the sensitizer and a 4-fold excess of thiol, the bis-addition product could be obtained, while the reaction with only 1.1 equiv of thiol allowed the introduction of two different thiols (Scheme 84).307a Interestingly, the possible β-fragmentation that could compete with the hydrogen transfer in the first addition does not alter the yield of this coupling reaction.

Scheme 82

monomers presenting a propargyl sulfide moiety, which might have a positive effect in reducing both the shrinkage and the shrinkage stress via a addition−fragmentation process similar to that taking place with allyl sulfides.304 Shrinkage and shrinkage stress are two of the main drawbacks of photopolymerizations of multifunctional monomers. The “thiol−ene” approach using allylsulfides in a radical addition−fragmentation chain transfer (RAFT) reaction proved to be very effective in reducing the shrinkage stress. Coupled with the “thiol−ene” methodology, the “thiol−yne” reaction allowed polymers with higher crossAJ


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Scheme 83

4.3. Simple Addition to Electron-Rich Ynoates and Ynamides

Scheme 84

The radical addition of ethanethiol to ethoxyacetylene was reported in the 1950s.310 More recently, Yorimitsu, Oshima, and co-workers have extended the scope of the radical addition of aryl thiols to ynamides.311 The addition could be achieved in an open-air reaction vessel at −30 °C in CH2Cl2 in the presence of substoichiometric amounts (ca. 10 mol %) of Et3B as radical initiator. The nature of the arenethiyl radical (electron-rich vs electron-poor substituted aryl group) had a dramatic influence on the course of the reaction (Scheme 85).311,312 Whereas electron-poor arenethiols (Ar = Ph, pScheme 85

BrC6H4, C6F5) gave excellent yields, electron-rich arenethiols (Ar = p-MeOC6H4, p-MeC6H4, o-MeC6H4) afforded the addition products in only low yields ( 300 nm). The reaction is quite general, with the thioselenation adducts being obtained in good to high yields (usually as a mixture of E/Z-isomers). Both terminal and internal alkynes

bis-chalcogenide adducts and a new chalcogen-centered radical (Scheme 97). Scheme 97

Alkynes present a higher reactivity than the corresponding alkenes in the reaction with dialkyl disulfides, probably due to the higher reactivity of vinyl radicals toward homolytic substitution at sulfur atoms as compared to alkyl radicals. In the 1960s, Heiba and Dessau reported the bis-thiolation of terminal alkynes with dialkyl disulfides. The reactions were carried out at room temperature in the presence of an excess of disulfide (3 equiv) under UV-light irradiation or, alternatively, by thermal initiation using t-butyl peroxide at 120 °C. Under these reaction conditions, the 1,2-dialkylmercaptoalkenes were obtained in high yields (Scheme 98).320 β-Sulfanyl alkenyl radicals could also be obtained by addition of thiyl radicals generated from diphenyl disulfide by SH2 AN


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could participate efficiently in the reaction, although alkylsubstituted alkynes were less reactive than the corresponding aryl-substituted acetylenes and required prolonged irradiation (Scheme 100, eqs a−c). It was observed that the prolonged

Scheme 101

Scheme 100

yields in the thiophosphination adducts were obtained in all cases (Scheme 101, eq c). The use of diaryl sulfides, however, gave generally better results than the corresponding dialkyl sulfides.324b The proposed mechanism involves the formation of a βsulfanylalkenyl radical by addition of a thiyl radical to the alkyne. The thiyl radical is generated either photochemically from diphenyl disulfide of thermally from diphenyl(phenylthio)phosphine. The vinyl radical is then trapped by diphenyl(phenylthio)phosphine (which can be formed by homolytic substitution at the phosphorus atom of a diphosphane with a thiyl radical), leading to the thiophosphination adduct and regenerating a thiyl radical that sustains the chain (Scheme 102). Scheme 102

irradiation might cause isomerization of the thioselenation adducts because their maximum of absorption is located in the near-UV region.321 The thiotelluration of alkynes was performed under similar conditions, and the corresponding thiotelluration adducts were obtained in good to high yields (Scheme 100, eqs d,e). In this case, filtering of the UV-light was required (hν > 400 nm) to prevent undesired photoinduced displacement of the PhTe group with a PhS group in the adducts.322 In both cases, the E/Z selectivity proved to be strongly dependent upon the nature of the alkyne (Scheme 100, eqs a−c and Scheme 100, eqs d,e). 4.4.1.d. Thiophosphination of Alkynes. The thiophosphination of terminal and internal alkynes has been reported independently by Ogawa and Oshima.324 Good to high yields were generally obtained from both internal and terminal alkynes, using either a binary system (PhS)2/(PPh2)2 in CDCl3 under irradiation at room temperature324a or diphenyl(phenylthio)phosphine under V-40 (1,1′-bis(cyclohexanecarbonitrile)) initiation in refluxing benzene.324b Aromatic alkynes were slightly more reactive than the corresponding alkyl-substituted alkynes. The binary system developed by Nomoto, Ogawa, and co-workers gave the thiophosphination products in good yields and moderate Eselectivity (Scheme 101, eqs a,b).324a Because of their airsensitivity, the resulting phosphine derivatives were generally oxidized by molecular oxygen or elemental sulfur to give the corresponding phosphine oxide (Scheme 101, eq a) or thiophosphine (Scheme 101, eq b), respectively. Oshima, Yoromitsu, and co-workers have studied the addition of various thiophosphines in the presence of V-40. Moderate to good

4.4.1.e. Reaction with a Carbon−Carbon Multiple Bond. Because thiols are good hydrogen donors, species that could possibly trap a vinyl radical in an intermolecular manner are limited to good radical traps. Accordingly, very few intermolecular trappings of β-sulfanylalkenyl radicals in a new carbon−carbon bond-forming reaction have been reported. The only example of which we are aware was disclosed by Montevecchi and co-workers in the late 1990s. The authors reported an isolated example of thiol-catalyzed trimerization of alkynes. In this reaction, benzeneethane thiol was mixed with phenylacetylene and ethyl propiolate, both used in large excess, and heated in the presence of AIBN. Under these reaction conditions, the β-sulfanylalkenyl radical intermediate was trapped by a second molecule of alkyne, as was the resulting AO


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radical. Final cyclization onto the vinyl sulfide moiety and βfragmentation gave arenes 191 and 192 (Scheme 103).95

cyclization to compete favorably with the fast hydrogen atom abstraction from the thiol. Under these conditions, cyclohexylidene sulfides were isolated as the major (or exclusive) products (Scheme 104, eq a,b). The formation of the six-

Scheme 103

Scheme 104

membered rings has been explained by a radical cascade involving the 5-exo cyclization of the intermediate vinyl radical, followed by ring expansion via 3-exo-trig cyclization onto the alkenyl sulfide moiety and subsequent fragmentation, before final quenching by thiophenol. However, trisubstituted alkenes, which should facilitate the 5-exo-trig cyclization, were found to be unreactive under these reaction conditions (Scheme 104, eq c). Although the efficiency of the approach proved to be strongly dependent upon the substitution at the alkene moiety, it is remarkable that those cyclizations were successful without the intervention of a Thorpe−Ingold effect. Cyclization of the related simple 1,7-enyne failed under these conditions, and only uncyclized vinyl sulfide was isolated. This approach has been used to access heterocyclic skeletons from easily prepared N-propargyl- and O-propargyl derivatives. Complications due to hydrogen abstraction from the activated propargylic (or allylic) position by the thiyl radical were observed (see sections 8.1.1 and 8.1.2). Nevertheless, successful cyclizations were reported in this series, giving access to a wide range of heterocycles. Simple propargyl allyl ethers cyclized selectively into either the methylenetetrahydrofuran or the methylenetetrahydropyran by changing the substitution of the alkene moiety.325 Montevecchi and co-workers have studied in great detail the reaction of propargyl allyl ethers with various thiyl radicals, bringing a clear understanding of the competing reactions involved in this process. The reaction proved to be highly substrate dependent; however, good yields of heterocyclic compounds could be obtained in some cases. For instance, the addition of 4-cyanotoluenethiol to ether 193, which possesses a terminal alkene, was achieved in refluxing benzene in the presence of substoichiometric quantities of AIBN and led to the tetrahydropyran 194 in 50% yield (mixture of E/Z isomers) via a 5-exo-trig cyclization followed by a rapid ring expansion (Scheme 105, eq a). Byproducts arising from rearrangement of the vinyl radical intermediate (vide infra) were also isolated. On the other hand, the presence of a phenyl substituent at the terminal position allowed the ring expansion to be prevented,

4.4.2. Intramolecular Trapping. The alkenyl radical formed by addition of a thiyl radical onto a carbon−carbon triple bond can engage further in intramolecular carbon− carbon bond-forming reactions. Alkenes, alkynes, but also oximes, hydrazones, or nitriles proved to be suitable partners to trap the highly reactive alkenyl radical in a ring-forming process, allowing a wide range of carbocycles and heterocycles to be formed. In some cases, aromatic rings could also be used as scavengers. The high reactivity of the vinyl radical intermediate allows intramolecular hydrogen atom transfer (HAT) to occur, thus offering the opportunity to create a new carbon−carbon bond at positions considered as unreactive. Specific substrates, designed for this purpose, have given excellent results. Not only can carbon−carbon bonds be formed but also carbon− heteroatom bonds. Indeed, alkenyl radicals obtained by addition of a thiyl radical have been successfully trapped by intramolecular homolytic substitution at sulfur and to a less extent by addition onto organic azides and ketimines. The synthetic potential of this very rich chemistry is illustrated in the following section. 4.4.2.a. Cyclization onto C−C Multiple Bonds. Intramolecular trapping of the vinyl radical intermediate by a C C bond has been reported to give small to medium-sized rings. The thiophenol-promoted cyclization of 1,6-enynes was reported in the 1980s by Broka and co-workers.242a The cyclization of simple enynes was achieved in moderate to good yields (based on thiol) provided a slow addition of PhSH was used. The slow addition of the thiol to a refluxing solution of substrate and AIBN in 2,2,5,5-tetramethyltetrahydrofuran (TMTHF) ensured the concentration of the reducing agent be kept at a sufficiently low level, thus allowing the desired AP


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Although not particularly attractive from the preparative standpoint, this study by Montevecchi and co-workers illustrates the versatility of thiols in radical chemistry by highlighting their reactivity in addition reactions, fragmentation processes, and hydrogen atom abstractions from activated positions. Ishibashi and co-workers developed a variant of these reactions, using diphenyl disulfide as the source of phenylthiyl radicals. The latter was obtained via the amine-mediated single electron transfer method by carrying out the reaction in the presence of tri-n-propylamine (40 equiv) and water (2 equiv). The addition onto enynes and propargyl allyl ethers led to cyclopentanes, as well as tetrahydrofurans and pyrrolidines in moderate to good yields (Scheme 107).271 The presence of

Scheme 105

and, in this case, the corresponding tetrahydrofuran 195 was obtained in 64% yield (Scheme 105, eq b). The corresponding homopropargyl allyl ethers gave a more complex mixture of products. Addition of thiol 197 onto enyne 196 gave a high yield of thioether 198 (Scheme 106, eq a),

Scheme 107

Scheme 106

water appeared to have an effect on the regioselectivity of the cyclization process. Its precise role in the reaction process, however, remains unclear. These reaction conditions give slightly higher yields than the addition of thiophenol under Et3B/O2 initiation onto similar substrates.268a Majumdar and co-workers have been particularly active in this field, having developed efficient routes to furo-coumarin derivatives,326 indole-annulated sulfur heterocycles,327 2Hpyrrolo[3,2-d]pyrimidines,328 as well as medium-sized rings such as oxepin,329 benzoxocine,330 and pyrimidine-fused azocine derivatives.331 The preparation of furo-coumarin derivatives326 and indole-annulated sulfur heterocycles327 was best performed in the presence of a slight excess of thiol (2 equiv) and stoichiometric quantities of AIBN (Scheme 108, eq a). The solvent proved to be crucial for the success of this reaction. The formation of furo-coumarin derivatives was observed exclusively in refluxing benzene, whereas tert-BuOH tends to favor instead an ionic Claisen rearrangement leading to a different product (pyrano-coumarin). On the contrary, indole-annulated sulfur heterocycles could be obtained in tertScheme 108

resulting from the rearrangement of intermediate 203, while the corresponding homopropargyl allyl ether 199 led to lower amounts of rearranged products 200 and 201 (ca. 17%) alongside the desired cyclic ether 202, which was isolated in only 28% yield (Scheme 106, eq b).325 Side products arising from hydrogen atom abstraction from the allylic position by the thiyl radical, as well as intramolecular hydrogen shifts, have also been observed. AQ


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BuOH, provided that an electron-withdrawing group was present at the nitrogen atom (Scheme 108, eq b). No βfragmentation leading to an allenyl sulfide was observed in these reactions. In both cases, the formation of the five-membered ring could be explained by the formation of a vinyl radical via the regioselective addition of the thiyl radical at the terminal position of the alkyne moiety, followed by a 5-endo-trig cyclization (Scheme 109, path a) or, alternatively, a 4-exo-trig

Scheme 110

Scheme 109

cyclization and subsequent neophyl rearrangement (Scheme 109, path b) very similar to the mechanism proposed to account for the cyclization of simple enynes (vide supra).332 For the formation of 2H-pyrrolo[3,2-d]pyrimidines (Scheme 110, eq a),328 oxepin,329 oxocine (Scheme 110, eqs b−d),329,330 and pyrimidine-fused azocine derivatives (Scheme 110, eq e),331 the reaction required a stoichiometric amount of AIBN (1.5−2 equiv). Slow addition techniques were needed for the preparation of 2H-pyrrolo[3,2-d]pyrimidines to ensure good yields by limiting intermolecular hydrogen abstraction from the thiol prior to cyclization. Interestingly, the oxepins were obtained as single E-isomers for the exocyclic carbon−carbon double bond (Scheme 110, eq b), as were some of the benzoxocines prepared by this approach (Scheme 110, eq c). Again, the solvent proved to be crucial in the cascade leading to benzoxocines as no cyclized compounds were formed in tBuOH, while high yields were obtained in benzene and using a lower concentration in thiophenol. Other heterocyclic-based oxocines and azocines have also been obtained with high levels of selectivity in favor of the Z-isomers (Scheme 110, eqs d,e).330b,331 Cyclizations of phenyl propargyl ethers leading to mediumsized rings (seven- or eight-membered rings) were high yielding, thus indicating that neither intermolecular abstraction from the propargylic position by the thiyl radical [see section 8.1] nor the competitive 1,6-hydrogen transfer [see section 4.4.2.e] from the activated allylic position of the vinyl radical intermediate took place to a significant extent. As previously mentioned, the formation of the medium-sized seven- and eight-membered ring could be explained by an endocyclization process, or alternatively by an exo-cyclization, followed by a homoallyl-cyclopropylcarbinyl rearrangement. Reversible competitive addition of the electrophilic thiyl radical

to the alkene moiety did not lead to any cyclized product, presumably due to the slowness of the cyclization step (Scheme 111). Alcaide and co-workers reported the preparation of mediumsized rings fused to β-lactams from Baylis−Hillman adducts, obtained via the condensation of optically pure 4-oxoazetidine2-carboxaldehydes with methyl vinyl ketone.333 The precursors were prepared in good to high yields and with high levels of stereoinduction, and their reaction with thiophenol under radical conditions led to the formation of the bicyclic [5.2.0]-, [6.2.0]-, and [7.2.0]-β-lactams in good yields (64−70%). The process was rationalized through a tandem radical addition/ Michael addition (Scheme 112). Related cyclizations mediated by tin-centered radical have also been reported, and better results were obtained in this case, in terms of both yield (80− 90% versus 64−70% in the thiyl-mediated reaction) and stereoselectivity. The latter was virtually complete in the tinmediated reaction, favoring the (E)- or the (Z)-isomer depending on the size of the forming ring.333 Radical cascades in which the carbon-centered radical formed during the cyclization process engaged further in a new carbon−heteroatom bond-forming reaction have been described. To our knowledge, efficient formation of a second carbon−carbon bond in such a radical cascade has not been reported thus far, although the tandem reaction appears to be feasible. AR


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Using the (PhS)2/(PhSe)2 binary system, that is, under nonreducing conditions, the cyclization of enynes and propargyl allyl ethers, such as 206, proved to be feasible, the functionalized five-membered rings being obtained in moderate to good yields. The tandem reactions were carried out under irradiation through Pyrex with a tungsten lamp (hν > 350 nm) to initiate the process (Scheme 114, eq a).321 Similarly,

Scheme 111

Scheme 114

thiophosphination of 1,6-enynes such as 207 could be achieved in CDCl3 with (PhS)2/(Ph2P)2. Subsequent oxidation of the resulting phosphine derivatives by S8 afforded the cyclized thiophosphonates in moderate yields (Scheme 114, eq b).324a The intramolecular reaction proved to be slightly less efficient than the related direct intermolecular trapping of the vinyl radical leading to the thiophosphination of the alkyne (see section 4.4.1.d), probably due to the lower reactivity of the primary alkyl radical formed after cyclization as compared to the vinyl radical intermediate obtained by addition of the thiyl radical onto the alkynyl moiety. Annulation Reactions. The carbon−carbon double and triple bonds required to achieve a radical cascade in which an alkenyl radical intermediate is trapped by intramolecular addition onto an alkene are not necessarily both present on the same precursor. Instead, they can be coupled during the addition of the thiyl radical if the starting thiol possesses the proper substituents. Examples of annulation reactions of this type have been reported but are limited to very specific substrates, which can accommodate the presence of both a reactive CC bond and a thiol functionality. Oshima and co-workers developed access to dihydrothiophene derivatives via a Et3B-promoted annulation reaction using allyl mercaptans 208 and terminal alkynes (Scheme 115).268a The course of the reaction is dramatically influenced by the presence of substituents at the CC bond, and complex mixtures of products were obtained by Montevecchi and coworkers with the nonsubstituted allyl mercaptan.335

Scheme 112

In the mid 1980s, Padwa and co-workers reported that the addition of thioacetic acid onto diynes such as N,N-bis-(2propynyl)benzene sulfonamide 204 led to 5-(phenylsulfonyl)5,6-dihydro-4H-thieno[3,4,c]pyrrole 205 via the homolytic substitution at the sulfur atom (Scheme 113). The second cyclization (intramolecular SH2) requires the E-configuration of the CC bond formed during the first cyclization process.334 Scheme 113

Scheme 115

AS


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generating spirocyclic radicals. Depending upon the nature of the aromatic substituent (aryl versus heteroaryl), the spirocyclic radical can undergo either cleavage of the benzylic C−S bond or ring-opening of the heteroaryl moiety (Scheme 118, eqs a,b). The migration of the aryl group leads stereoselectively to triand tetrasubstituted alkenes in moderate to good yields.

The addition of benzenethiol or diphenyl disulfide to acetylene, phenylacetylene, and prop-2-yn-1-ol gave benzothiophene derivatives under drastic conditions (500−590 °C) via the intramolecular cyclization of the vinyl radical intermediate onto the aromatic ring of the thiol and subsequent aromatization.336 Montevecchi and co-workers have reinvestigated this reaction and proved that the thermal reactions of diphenyl disulfide with various phenylacetylenes promoted by di-tert-butyl peroxide (2 equivalents) could be achieved at lower temperature (110−150 °C), providing a route to substituted benzo[b]thiophenes. Because the process is not a chain reaction, large amounts of initiator are required. However, the yields of benzothiophenes were influenced by the nature of the alkyne (10−75%, nine examples), the variations of the results being difficult to rationalize (Scheme 116).95,99,337

Scheme 118

Scheme 116

The proposed mechanism involves the generation of a phenylthiyl radical via homolytic substitution at the sulfur atom of diphenyl disulfide with a methyl radical formed by thermal decomposition of di-tert-butyl peroxide. Addition of the thiyl radical to the alkyne gives a β-sulfanylalkenyl radical intermediate, which then undergoes cyclization onto the aromatic substituent of the sulfur atom. Aromatization of the resulting radical affords the benzothiophene derivatives (Scheme 117).

The cyclization of the vinyl radical onto the aromatic substituent could occur either at the ipso or ortho position. The cyclization at the ipso position is favored and leads to a resonance-stabilized radical intermediate. An extra stabilization by the OMe and CN substituents tends to accelerate the cyclization onto the aromatic ring, thus increasing the proportion of rearranged products. A related mechanism could account for the formation of 213. However, in this case, the spirocyclic radical intermediate undergoes a βfragmentation that leads to the ring-opening of the initial aromatic ring (Scheme 119). 4.4.2.b. Intramolecular Addition to the CN Bond of Oximes and Hydrazones. Cyclizations of carbon-centered radicals onto the carbon atom of the CN bond of oximes and hydrazones represent a useful approach to form functionalized cycloalkanes. The cyclization onto hydrazones is a very fast process with high rate constants (108 s−1 for the formation of five-membered rings), which makes them one of the fastest radical cyclizations.245 Such functionalities have been used to trap carbon-centered radicals formed by addition of a thiyl radical onto alkynes. Neither the ionic addition of the thiol nor radical addition onto the CN bond have been shown to compete with the addition of the thiyl radical onto the alkyne. Imines also take part in the reaction, and for very specific substrates, examples of addition at the nitrogen atom have been reported. The intramolecular trapping of β-sulfanylalkenyl radicals by addition onto an oxime is the key step for a number of elegant syntheses reported by the Keck group in the 1990s. The total synthesis of lycoricidine340 and narciclasine340b has been

Scheme 117

Montevecchi and co-workers have extensively investigated the skeletal rearrangements of alkenyl radicals formed by the addition of benzyl,95,325,335,338 allyl,335 and heteroarylmethane thiols339 onto terminal alkynes. For the reaction with benzyland heteroarylmethane thiols, the authors have demonstrated that the β-sulfanylalkenyl radical intermediates are prone to rearrange via a 5-exo-cyclization onto the aromatic ring, AT


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The more hindered ketoximes were also found to be suitable radical acceptors, and, in this case, a quaternary center is created via the cyclization of the vinyl radical intermediate. Alonso and co-workers reported a series of 5-exo-trig and 6-exotrig cyclizations, which were based upon this strategy.341 For instance, the thiyl radical generated from thiophenol under irradiation (450 W medium pressure mercury lamp) promoted the cyclization of the ketoxime ether 217 (Scheme 121, eq a).

Scheme 119

Scheme 121

achieved from D-gulonolactone using this strategy (9 steps and 44% overall yield, 12 steps and 26% overall yield, respectively). The key radical cyclization was best achieved by carrying out the reaction at room temperature in toluene under sunlamp irradiation (Scheme 120). The addition of the thiyl radical onto Scheme 120 Although cyclized compound 218 was isolated in only moderate yield (55%), together with uncyclized vinyl sulfide 219 (15%), complete regioselectivity was observed for this cyclization process, the addition of the thiyl radical taking place exclusively at the less hindered position of the terminal alkyne. High dilutions were needed to limit the intermolecular hydrogen abstraction from the thiol by the β-sulfanyl alkenyl radical intermediate. The presence of a radical stabilizing substituent at the terminal position of alkynes such as 220, for which the mode of cyclization (5-exo versus 6-exo-trig) depends directly upon the regioselectivity of the intermolecular addition onto the alkyne, drove the addition of the thiyl radical at the remote position, thus increasing the selectivity in favor of the six-membered rings. A complete reversal in the regioselectivity was observed with a phenyl substituent. Accordingly, ketoxime ether 220 afforded 221 in 75% yield from the regioselective addition of the thiyl radical onto the alkyne, followed by a 6exo-trig cyclization (Scheme 121, eq b). Under these conditions, no competitive 1,5-hydrogen atom transfer (see section 8.1.1) from the α-alkoxy position has been observed. Like oximes ethers, hydrazones proved to be very useful radical traps in these tandem reactions. Hydrazones proved to be as reactive as the oxime ethers, or even slightly more reactive. The reactivity of hydrazones (as well as oxime ethers) as traps for vinyl radicals generated by addition of thiophenol to terminal alkynes has been studied by El Kaim and co-workers toward the end of the 1990s.246a Cyclopentanes, as well as tetrahydrofurans, could be obtained in good yields from acyclic hydrazones such as 222 by using only a slight excess of thiophenol and small amounts of AIBN as an initiator (Scheme 122, eq a). The nature of the hydrazine component was found

disubstituted alkyne 214 proved to be highly regioselective, with the addition occurring exclusively at the remote position from the phenyl substituent, thus delivering the more stable benzylic alkenyl radical. The latter cyclized efficiently onto the CN bond of the oxime ether moiety. Slightly lower yields were obtained at higher temperatures, and, more surprisingly, the reaction time were also much longer (48 h at 65 °C versus 2 h at room temperature for complete consumption of the starting material). This observation was attributed to an increase in the rate of β-scission at high temperature. Worthy of note is the fact that the Bu3SnH-mediated reaction led to the opposite regioselectivity for the intermolecular addition, presumably due to steric effects. The syntheses of lycoricidine and narciclasine were completed in two and five steps, respectively, from intermediates 215 and 216. AU


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a vinyl radical that could then add to the aromatic cyano group in a 5-exo-dig manner (Scheme 124). Upon hydrolysis of the

Scheme 122

Scheme 124

to have some influence, as illustrated by the cyclization of hydrazone 223 (Scheme 122, eq b). The formation of sixmembered rings proved to be less general, and in this case hydrazones gave better results than the corresponding oximes. However, this trend is not general because the reverse order of reactivity has been observed with other substrates. Friestad reported a related thiyl-mediated radical addition/ cyclization using enantiomerically pure α-hydroxyhydrazones in which the alkyne and the hydrazone moieties were linked using a silyl ether.342 The resulting cyclic silanes were not isolated but were directly engaged in desilylation reactions with n-Bu4NF in THF, which was found to give higher yields than KF/MeOH. Surprisingly, desilylation with concomitant elimination of the sulfide moiety was not observed, and, instead, only the vinyl sulfides arising from a protodesilylation were isolated (Scheme 123). The 1,2-amino alcohols were obtained with good to high

resulting ketimine derivative, the ketone 225 was isolated. Attempts to cyclize linear alkyl nitriles were not successful under the same reaction conditions. 4.4.2.c. Intramolecular Attack onto the Nitrogen Atom. The addition of carbon-centered radicals onto azides has been known for a number of years.344 In particular, the intramolecular addition of carbon-centered radical at the internal nitrogen atom of azides offers the possibility to access Nheterocycles, such as pyrrolidines, after extrusion of nitrogen gas from the intermediate.344c,345 Aryl azides having an alkynyl side chain at the ortho position could be converted into indoles using the thiol-mediated addition/cyclization sequence. Here again, the regioselectivity for the intermolecular addition process needs to be controlled, and the presence of aryl substituents gave the best results.346 Thiophenol gave better results than alkanethiols for which the addition onto the disubstituted alkyne is not reversible and thus not completely regioselective, leading to a mixture of products (Scheme 125, eqs a,b). The proposed mechanism proceeds as follows: reversible addition of the phenylthiyl radical onto the carbon−carbon triple bond of 226 leads to two different 2-sulfanylvinyl radicals, only one of which is able to cyclize onto the azido group.

Scheme 123

Scheme 125

levels of diastereoselectivity, and this strategy was applied to an asymmetric synthesis of aminosugar N-trifluoroacetyl-L-dausonamine.342b Successful applications involving nitrile radical traps have been disclosed.343 In this context, some examples of thiolmediated addition/cyclization reactions involving phenyl acetylene derivatives having a cyano group at the ortho position have been studied by Montevecchi and co-workers.338 The key for the success of this reaction is the control of the regioselectivity in the addition of thiyl radical. Indeed, for the vinyl radical intermediate to undergo cyclization onto the cyano group, the latter must be located at the proper position. Accordingly, only alkynes such as 224, which present a second aromatic substitution on the alkyne to drive the addition, led to AV


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Following nitrogen loss from the triazenyl radical 228 intermediate and hydrogen abstraction from thiophenol by the resulting aminyl radical 229, indole 227 is obtained (Scheme 126).

Scheme 127

Scheme 126

Scheme 128

Favorable geometric (and maybe also stereoelectronic) factors are required to facilitate the cyclization, which has to compete favorably with both the intermolecular hydrogen atom abstraction from the thiol and the skeletal rearrangements (vide supra).346,347 However, these factors are also likely to accelerate the thermal intramolecular 1,3-cycloaddition between the alkyne and the azide, as was observed with the simple and linear hexynyl azides. 4.4.2.d. Intramolecular Chalcogenation: SH2 at Sulfur. On the basis of the pioneering work of Crich and co-workers,348 Spagnolo and Benati have reported an elegant method for generation of acyl-,349 carbamoyl-,350 and alkyl radicals351 under tin-free conditions. The approach consists of a regioselective addition of a thiyl radical onto the terminal alkyne of thioesters 230 derived from 4-pentynyl sulfides, followed by intramolecular homolytic substitution at the sulfur atom.180 Beside the carbon-centered radical, the cyclization gives thiophene 231 in good to high yields (Scheme 127). Carbon-centered radicals released in this process could be trapped either in an intermolecular manner by hydrogen atom abstraction from the thiol, addition onto an unsaturated partner, or intramolecularly to give carbo- and heterocycles. This method has been extended to the generation of phosphorus-centered radicals. Alkyl 4-pentynyl sulfides were easily obtained from the corresponding alkyl halide and subsequently reduced into the alkanes in nearly quantitative yields, thus offering an alternative for the removal of a halogen atom from a complex molecule without the need for a highly nucleophilic hydride (Scheme 128, eq a).351 The best results were obtained in refluxing toluene by using a slow addition of thiophenol to limit the

intermolecular hydrogen atom abstraction from the thiol by the alkenyl radical prior to intramolecular homolytic substitution. Using this approach, aliphatic and aromatic aldehydes have also been obtained, this time from the corresponding 4-pentynylthiol esters.349,351 The decarbonylation of the acyl radical intermediate proved to be difficult to prevent when secondary and tertiary carbon-centered radicals could be formed during this process. The example depicted in Scheme 128, eq b,349b is a specific case for which the decarbonylation could be prevented due to the specific nature of the tertiary radical that would result from the decarbonylation process (bridgehead radical). Intermolecular trapping of carbon-centered radicals generated by this approach proved feasible, as illustrated in Scheme 128, eq c, but will presumably be limited in scope due to the competing addition of the thiyl radical onto the radical trap. To our knowledge, a screening of different classes of thiols able to AW


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competing reduction of the vinyl radical intermediate was observed but remained a minor process (300 nm) to form the thiyl radicals gives, in most cases, better results than does thermal initiation with AIBN, which leads to the formation of 2-cyanopropyl radical derived byproducts. As illustrated in Scheme 193 with methylenecyclopropanes 349 and 350, depending on the nature of the carbon-centered radical intermediate, electron-rich (Scheme 193, eq a)431,454a,b,d and electron-poor alkenes (Scheme 193, eq b)454c can both take part in the reaction. The nature of the thiyl radical used to mediate these annulation processes influences the diastereoselectivity of the reaction.431 BP


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Scheme 195

of the carbon-centered radical intermediate prior to cyclization onto the thioester moiety, which is a reversible process. In this regard, S-phenyl thioesters proved to be better radical traps than the corresponding S-alkyl thioesters, presumably because the β-fragmentation from β-phenylsulfanyl alkoxyl radicals intermediate 356 is faster than that for the corresponding βalkylsulfanyl alkoxyl radicals, thus competing more favorably with the fragmentation of the carbon−carbon bond (Scheme 197). The cleavage of the carbon−carbon bond can be limited

cyclopropanone 353 from strained cyclopropyl alkoxyl radical intermediate 352 was not observed, and only rearranged product 354 resulting from the C−C bond cleavage could be detected. Less strained cycloalkanones could be prepared using this approach. Kim and co-workers demonstrated that simple cyclopentanones and cyclohexanones (Scheme 196, eqs a,b), as well as polycyclic ketones (Scheme 196, eq c), can be prepared from thioesters such as 355 upon irradiation in benzene in the presence of Bu6Sn2 (1.1 equiv).457 The best yields were obtained for the formation of cyclopentanones, and the major side-reaction was the reduction

Scheme 197

Scheme 196

by using the related selenoesters, which are better radical traps.457 In the case of more strained cyclopropyl alkoxyl radical intermediates, the cleavage of the carbon−sulfur bond cannot compete, and the carbon−carbon bond scission becomes the main reaction pathway (vide supra). 5.2.4.b. Cyclization to Benzoimidazole Derivatives. Caddick and co-workers studied the possibility to access fused [1,2,a]indoles through the cyclization of carbon-centered radicals onto sulfur-substituted indoles.458 These ipso-substitutions carried out in refluxing toluene in the presence of nBu3SnH/AIBN are moderately successful and somewhat limited because only the formation of six-membered rings could be achieved in synthetically useful yields (Scheme 198). However, better results have been obtained with the corresponding sulfones458c and sulfoxides.458 Bowman and co-workers have extended this ipso-substitution to include 2-(benzenesulfanyl)-benzimidazole derivatives, for which the cyclization of the alkyl radical onto the aromatic ring could be achieved in low to moderate yields, depending on the size of the forming ring (Scheme 199).459 Attempts to extend this methodology to solid-phase synthesis have also been reported, but this approach was not very successful.459c BQ


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Scheme 198

Scheme 201

Scheme 199

substoichiometric quantities of AIBN as a radical initiator gave allyl alcohols 359 in moderate to high yields (Scheme 202). Scheme 202 5.2.5. Other Types of Fragmentation: Desulfurization Reactions. Desulfurization of thioethers can be achieved under radical conditions with tributyltin hydride. The reaction proceeds via a homolytic substitution at the sulfur atom and proved to be efficient for the generation of a wide range of carbon-centered radicals.180 Homolytic substitution (SH2) reactions at the sulfur atom of thiiranes lead to a βstannylsulfanyl carbon-centered radical that undergoes βfragmentation to give olefins (Scheme 200).460 The reaction Scheme 200

In the 1980s, the Nicolaou group reported access to cis-fused oxobicyclic systems based upon the β-fragmentation reaction of α-alkoxy-β-alkylthio radicals. The latter were generated from thioethers such as 360 in the presence of n-Bu3SnH/AIBN by homolytic substitution at the sulfur atom (Scheme 203).464 Scheme 203

is carried out using a slow addition of a solution of the thiirane and traces of AIBN in benzene to a refluxing solution of Bu3SnH in benzene. Even under these conditions, the transient species could not be trapped by hydrogen abstraction from the tin hydride, demonstrating that, as for other types of β-sulfanyl alkyl radicals, the β-fragmentation leading to a R3Sn−S• radical species is a very fast process. Nevertheless, substantial isomerization has been observed from stereodefined thiiranes. Desulfurization can also be achieved by generating a radical species at the β-position to an aryl- or alkylthio substituent. Comins and co-workers have utilized this strategy to introduce a CC bond regioselectively in piperidine derivatives (Scheme 201).461 Ono and co-workers used a radical denitration reaction417,462 to access allyl alcohols.463 γ-Phenylthio β-nitroalcohols such as 357 were prepared from nitroalkenes in the presence of thiophenol, an aldehyde, and a small amount of tetramethylguanidine. Following acylation of the hydroxyl group, treatment of 358 in refluxing benzene with an excess of n-Bu3SnH and

In the early 1980s, Ueno and co-workers studied the relative stability of various sulfur-centered radicals using competitive elimination techniques.465 Considering that the conversion of allylsulfides into allylstannanes proceeds via an addition− fragmentation process, the authors postulated that a similar behavior should be observed in related system such as αketosulfides. Competitive elimination reactions were carried out with ketones possessing two different sulfur substituents at the α-position using n-Bu3SnH/AIBN in refluxing benzene. Surprisingly, the elimination of PhS• was found to be more BR


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efficient than elimination of RSO2•. On the other hand, the carbon−S(O)R bond proved to be more labile (Scheme 204).

6.1. General Trends

Heteroatom-centered radicals have also been found to react with isonitriles. In the 1970s, Blum and Roberts were able to characterize the adducts between alkyl isonitriles and oxygen-, silicon-, phosphorus-, and sulfur-centered radicals using electron paramagnetic resonance (EPR) spectroscopy.473 The addition of a thiyl radical onto an isonitrile generates an αthioimidoyl radical (Scheme 206).474 Variable-temperature

Scheme 204

Scheme 206

EPR spectra of representative thioimidoyl radicals have been obtained in liquid cyclopropane at low temperature (150 K) by photolysis of dialkyl disulfides in the presence of alkane isonitriles with g-factors (2.0008−2.0014) consistent with a σstructure for α-thioimidoyl radicals.475 Thioimidoyl radicals can, in principle, undergo different transformation, depending upon the reaction conditions. For thioimidoyl radicals 363 generated from an isonitrile and a thiyl radical, hydrogen atom abstraction from the thiol to give a thioformimidate 364 can occur (Scheme 207, eq a). Alternatively, in the presence of a suitable radical acceptor, addition onto the carbon−carbon (or carbon−heteroatom) multiple bond can lead to the formation of a new carbon− carbon bond (Scheme 207, eq b). On the other hand, in the absence of a good radical trap for the thioimidoyl radical, the latter evolves by fragmentation of the C−S bond, leading to an isothiocyanate 365 with the concomitant release of a carboncentered radical (Scheme 207, eq c). On the contrary, the cleavage of the C−N bond leading to thiocyanate 366 is usually not observed under these reaction conditions (Scheme 207, eq d). Depending upon both the nature of the isonitrile R1−NC (R1 = aryl, alkenyl or alkyl) and the thiyl radical R2S•, the αthioimidoyl radical intermediates thus either have been trapped in an intra- or intermolecular fashion or have led to isothiocyanides and a carbon-centered radical via β-fragmentation.

However, no direct proof supporting the formation of a tinenolate was given, and the alternative SH2 mechanism cannot be ruled out. Actually, the abundant literature describing SH2 reactions at the sulfur atom for the generation of stabilized carbon-centered radicals α-ketosulfides tends to indicate that an alternative mechanism involving SH2 reaction at the sulfur atom is more likely. The alternative SH2 mechanism also accounts for the lack of reactivity of the sulfone 362 because it has been recently proven that homolytic substitution at the sulfur atom in sulfones is extremely slow due to the absence of lone pairs on the sulfur atom.466

6. ADDITION OF THIOLS TO ISONITRILES Isonitriles have an electronic structure similar to that of carbon monoxide, and, accordingly, they have been found to participate in addition reactions with carbon-centered radicals. In contrast to most other addition processes onto CC and CX bonds, the addition onto carbon monoxide and isonitriles leads to a new radical species without breaking of the π-bond.467 This allows original radical cascades to be designed, as illustrated by the preparation of quinolines,468 campothecins,469 mappacine470 and mappacine analogues,471 and luotonin analogues472 reported by Curran and co-workers during the past two decades (Scheme 205).

6.2. Intermolecular Trapping

6.2.1. Simple Addition versus Addition−Fragmentation. The addition of thiols to isonitriles was first reported at the end of the 1960s.476 The fact that the reaction was accelerated in the presence of a radical initiator or under UVirradiation was in good agreement with a radical chain mechanism.115,476 Alkyl, benzyl, and aryl thiols were found to add efficiently to isonitriles, giving either thioformimidates, isothiocyanates, or a mixture of both, depending principally upon the nature of the thiol used. Primary alkyl and aromatic thiols led to thioformimidates, exclusively, whereas benzylthiol and tertiary thiols gave isothiocyanates and alkanes (Scheme 208). On the other hand, a mixture of these products was obtained with secondary alkanethiols. The authors proposed a radical chain mechanism with an α-thioimidoyl radical intermediate, which can either undergo C−S β-fragmentation, thus leading to isothiocyanides, or hydrogen atom abstraction from the thiol to give the corresponding thioformimidate. Blum and Roberts,473 and later Walton and co-workers,475 have demonstrated that the cleavage of the C−S bond by βscission in thioimidoyl radicals is indeed a fast process with rate

Scheme 205

BS


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Scheme 207

the corresponding thioisocyanate, which can be then easily removed from the reaction mixture. Interestingly, the desulfurization could also be achieved at room temperature using Et3B/O2 as an initiator. In the case of electrophilic carbon-centered radical intermediates, for which hydrogen abstraction from the thiol is relatively slow, the reaction carried out in the presence of an excess of electron-rich alkene as a radical trap allowed the formation of the corresponding adducts in good to high yields. Enol ethers, silyl enol ethers, and vinyl silanes have been found to participate efficiently in this reaction (Scheme 210, eqs a,b). A single example of cyclization has also been reported.479

Scheme 208

constants kf in the range 105−106 s−1 at 298 K.475 Although the thioimidoyl radical formed in the addition of t-BuS• to t-Bu-NC could be observed by EPR spectroscopy in liquid cyclopropane at 150 K, only the tert-butyl radical resulting from β-scission was observed at temperatures above 200 K. The N-substituents proved to have only little influence on the β-fragmentation rate, while the nature of the substituent at the sulfur atom proved to be crucial. In this case, the higher is the stabilization of the released carbon-centered radical, the greater is the rate of βscission. In contrast to the related reaction of phosphorus-477 and tin-centered radicals478 with isonitriles, no fragmentations of the C−N bond were observed with thiyl radicals. This observation has been supported by kinetic studies and density functional theory (DFT) calculations, which have shown that βfragmentation by C−S bond scission is always favored as compared to C−N scission, regardless the nature of the substituents at the sulfur and nitrogen atoms.475 Taking advantage of this property, Nanni, Minozzi, and coworkers developed an efficient reductive desulfurization of functionalized thiols using commercially available tert-butyl isocyanide.479 High yields in desulfurized compounds were obtained from a range of thiols, including primary alkanethiols (Scheme 209), provided a slow addition of a solution of the thiol was used. The procedure is quite general, and the workup was facilitated by the low boiling point of both the isonitrile and

Scheme 210

Scheme 209

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6.2.2. Double Chalcogenation Reactions. Ogawa and co-workers have studied the chalcogenation of α-thioimidoyl radicals. Upon irradiation with a 500 W tungsten lamp and under neat conditions, diphenyl disulfide was found to add onto 2,6-xylyl isocyanide 367, leading to the 1,1-bisthiolation product 368 in good yield (Scheme 211, eq a).480 On the other

Scheme 212

Scheme 211

Scheme 213

Similarly, the thiotelluration of isonitriles could be achieved using a (PhS)2/(PhTe)2 binary system. The reaction proved less general, leading to the thiotelluration products in good to high yields with aromatic isonitriles bearing electron-withdrawing groups, such as p-NO2, p-CF3, and p-CN (Scheme 214). Aliphatic isonitriles and electron-rich aromatic isocyanides failed to give the thiotelluration products.482

hand, the reaction carried out in the presence of solvent led to a mixture of 1,1-bisthiolation product and isothiocyanate, presumably due to the formation of p-PhSC6H4SH from diphenyl disulfide under the reaction conditions.481 Alkyl isonitriles did not give any bis-thiolation product under these reaction conditions, but the use of a binary system (PhS)2/ (PhSe)2 afforded the bis-thiolation products in moderate to good yields from aliphatic (primary and secondary) isonitriles (Scheme 211, eq b). Tertiary isonitriles are unreactive under the same conditions.480 Interestingly, under the same reaction conditions, the thioselenation adducts produced from aromatic isocyanides were stable and could be isolated in high yields (Scheme 211, eqs c,d). The proposed mechanism involves the homolytic cleavage of the selenium−selenium bond upon irradiation to give phenylselanyl radical (PhSe•) 369, which reacts with diphenyl disulfide to give PhSeSPh 370 and a benzenethiyl radical. The addition of the thiyl radical onto the isonitrile results in the formation of α-thioimidoyl radical 371, which can be trapped either by diphenyl diselenide or by PhSeSPh to give the thioselanylation or the bis-thiolation adducts 372 and 373, respectively. Under the reaction conditions, 372 obtained from alkyl isonitrile is believed to be unstable, and thus cleavage of the carbon−selenium bond regenerates the α-thioimidoyl radical 371, which reacts with a thiyl radical to furnish a stable product 373 (Scheme 212). The thioselanylation adducts have been used in [2 + 2]cycloadditions for the preparation of polysubstituted β-lactams. Selective cleavage of the carbon−selenium bond could be achieved via homolytic substitution (SH2) at the selenium atom using tin-centered radicals. For instance, the fragmentation method with tributylallyltin allowed further functionalization of the azetidinone ring (Scheme 213).480

Scheme 214

6.3. Intramolecular Trapping

α-Thioimidoyl radicals obtained by addition of a thiyl radical onto an isonitrile are, in principle, reactive enough to engage in new carbon−carbon bond-forming processes. The key for the success of such a transformation lies in the comparison between the rate for the addition and those for the possible sidereactions. The competing reactions are the intermolecular hydrogen abstraction (if a thiol is used) and/or the βfragmentation by cleavage of the weak C−S bond in the thioimidoyl radical. As was already observed in the 1970s, the nature of the thiol is crucial for bimolecular processes (the hydrogen atom from the thiol leading to isothioformimidates) to compete favorably with the β-fragmentation giving isothiocyanates.115,476 The use of thiols RSH releasing stabilized radicals (resonance-stabilized radicals or tertiary alkyl radicals) led exclusively to isothiocyanates, and in this case the corresponding α-thioimidoyl radicals could not be observed by EPR spectroscopy, even at very low temperatures. BU


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In contrast, aryl and primary alkyl mercaptans, for which the fragmentation would give a nonstabilized radical, evolved mainly by hydrogen abstraction from the thiol. However, under certain reaction conditions, fragmentation still occurred (see Scheme 209). The relatively high rate constants for the fragmentation (105−106 s−1) do not facilitate the design of reactions involving an intermolecular trapping of the αthioimidoyl radicals. On the other hand, 5-exo cyclizations have rate constants lying in the same range as the fragmentation of α-thioimidoyl radicals, and, accordingly, some very efficient and elegant examples of intramolecular trapping have been disclosed. They will be discussed in the following section. 6.3.1. Cyclization onto Alkenes and Alkynes. Nanni and Walton have studied by EPR spectroscopy the addition of butenesulfanyl radicals onto a range of alkyl isonitriles. The authors showed that the α-thioimidoyl radicals formed as intermediates during the process were able to cyclize in a 5-exo mode. The butenesulfanyl radical was generated from the corresponding disulfide in cyclopropane, a solvent with a very poor hydrogen donor ability; thus no hydrogen atom abstraction was expected to compete with the β-fragmentation. This led to the formation of 3-butenyl radical, and subsequent cyclization onto the alkene moiety. Although the cyclization is observed at 230−260 K, the β-fragmentation dominates at higher temperatures and limits considerably the synthetic applications.475,483 Aromatic or even aliphatic isonitriles having an alkenyl or alkynyl side chain are synthetically more useful upon reaction with primary aliphatic and aromatic thiols. For instance, indoles have been prepared in good yields by addition of thiyl radicals to aromatic isocyanides having an alkenyl side chain at the ortho position (Scheme 215, eqs a,b). The reactions

Scheme 216

The following mechanism accounts for the formation of the bis-thiolation product. Upon visible light irradiation, the tellurium−tellurium bond of diphenyl ditelluride is cleaved, leading to phenyltelluryl radicals (PhTe•). The latter react with diphenyl disulfide to form PhSTePh, which undergoes homolytic cleavage of the sulfur−tellurium bond to give a phenylthiyl radical (PhS•). The addition of PhS• onto the aromatic isonitrile leads to α-thioimidoyl radical 375 that undergoes cyclization in a regioselective 5-exo-trig manner, thus generating a new carbon-centered radical 376. Homolytic substitution at the tellurium atom of either diphenyl ditelluride or, alternatively, the mixed species PhTe−SPh leads to the thiotelluration 377 or bisthiolation 378 adducts, respectively. Following migration of the carbon−carbon double bond to give the aromatic indole ring 379, the cleavage of the benzylic carbon−tellurium bond, which is likely to be unstable under the reaction conditions, occurs, thus generating carbon-centered radical 380. The latter reacts either with diphenyl ditelluride to give back 379 or, alternatively, with PhTe−SPh to give indole 374. The latter is stable under the reaction conditions and accumulates (Scheme 217). Scheme 217

Scheme 215

were carried out at 100 °C in acetonitrile in the presence of AIBN as a radical initiator. The best results were obtained with an excess (5 equiv) of the thiol. Ethanethiol, 2-mercaptoethanol, and thiophenol gave good results; however, the subsequent desulfurization was best achieved from 2-thioindole intermediates bearing an ethanesulfanyl moiety. Interestingly, the selectivity in favor of the 5-exo-trig cyclization proved to be higher than that for the related tin-mediated cyclization, for which products resulting from both 5-exo-trig and 6-endo-trig processes were obtained.484 The reaction carried out under nonreductive conditions, that is, from disulfides instead of thiols, allowed for the trapping of the carbon-centered radical resulting from the cyclization. Using a binary system (PhS)2/(PhTe)2 and under irradiation with visible light, aromatic isonitriles having an alkenyl side chain at the ortho position were converted into bis-thiolated indoles. The preparation of quinolines using this approach proved to be less successful, the product resulting from a bisthiolation being obtained in only low yields (Scheme 216).482

The preparation of indoles from aryl isonitriles having an alkynyl side chain at the ortho position also proved feasible, and high yields have been obtained with silylated alkynyl moieties. The addition of a second molecule of thiol was observed, through either a radical or an ionic mechanism (Scheme 218).485 BV


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pioneering work of Ito and co-workers,115 they demonstrated the utility of isonitriles for the formation of pyrrolidines and related compounds.487 The cyclization of alkenyl-substituted isonitriles such as 384, easily accessible from glycine imines, could be achieved in high yields using either a primary alkanethiol (1.15 equivalent) or thiophenol. The reactions were carried out with AIBN as an initiator, using either thermal or photochemical activation. The best results with thiophenol were obtained at relatively low temperatures (10−20 °C), but the best compromise to maintain high yields and short reaction times was shown to be 40 °C.487a With methyl mercaptoacetate, the temperature needed to be lowered to −60 °C for the cyclization to compete favorably with the β-fragmentation of the α-thioimidoyl radical intermediate.487b The cyclization carried out in the presence of ethanethiol gave dihydropyrrole derivatives 385, while the reaction with mercaptoethanol afforded instead pyroglutamates 386, presumably via a thermal rearrangement of the pyrroline intermediate 387 (Scheme 221,

Scheme 218

The cyclization onto a carbon−carbon triple bond, however, generates a highly reactive alkenyl radical. As was already mentioned (see section 4.4.2.e), these radicals are prone to undergo intramolecular hydrogen shifts. For instance, the addition of cyclohexanethiol onto isonitriles 381 led to a mixture of compounds, among which spiro-derivatives 382 and 383 could be characterized (Scheme 219).486

Scheme 221

Scheme 219

The formation of spiro-compounds 382 and 383 was explained by a radical cascade involving a 1,5-hydrogen atom transfer (1,5-HAT) to form a radical, which undergoes 5-endotrig cyclization onto the trisubstituted alkene (Scheme 220). Bachi and co-workers reported very efficient cyclizations of α-thioimidoyl radicals onto linear, nonaromatic, isonitriles having an alkenyl or an alkynyl moiety. Following the Scheme 220

eqs a,b).487a−c On the other hand, the reaction with t-BuSH led to the formation of isothiocyanate derivatives 388, which could be cyclized into the corresponding pyrothioglutamate 389 in the presence of n-Bu3SnH and AIBN (Scheme 221, eq c). The cyclization of isonitriles having a silylated-alkynyl side chain also proved to be very efficient, although higher temperatures were required (Scheme 221, eq d).487b Moderate to excellent BW


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levels of stereocontrol have been observed for the cyclization process,487b,c as illustrated by the cyclization of syn-isonitrile 384 depicted in Scheme 221. The reaction times of these cyclization could be dramatically reduced by carrying out the reaction under microwave irradiation.488 The fragmentation method using an allylsulfide (see section 5.2.1) as the alkenyl moiety allows one to carry out the reaction with only a catalytic quantity of the thiol.487b This methodology was applied to the synthesis of racemic,487d,e as well as enantioenriched,487f,g kainic acid. Isonitrile 390 was converted into dihydropyrrole 391 in high yield in the presence of a catalytic amount of EtSH and AIBN (Scheme 222). Although

Scheme 223

Scheme 222

Scheme 224

isomerization of vinylpyrrolines into the more stable alkylidenepyrrolines was observed with other substrates, no migration of the double bond to form the conjugated compound 392 was observed in this case.487b This reaction proceeds via the intermolecular addition of a thiyl radical to 390 to generate the carbon-centered αthioimidoyl radical 393. The latter cyclizes onto the allylsulfide moiety to form a new radical species 394, which undergoes βfragmentation leading to 391 and regenerating the thiyl radical that propagates the chain. In a subsequent step, double bond migration might occur to give the conjugated alkylidene pyrroline, which is, in most cases, the more stable product (Scheme 223). 6.3.2. Cyclization to Nitriles. Nanni and co-workers have shown that α-thioimidoyl radicals generated by addition of a thiyl radical bearing a cyano group at the β-position onto aromatic isonitriles could undergo cyclization onto the nitrile. As was previously discussed, this cyclization has to be faster than the competing intermolecular hydrogen abstraction (if a thiol was used as a source of thiyl radicals) and the βfragmentation leading to isothiocyanates. Accordingly, only poor results were obtained with cyano-substituted alkanethiols such as 395, although thienoquinoxaline 396 could be isolated in 14% yield, thus demonstrating that the α-thioimidoyl radical intermediate was reactive enough to cyclize onto the CN triple bond (Scheme 224, eq a). Better results were obtained by photolysis of aromatic disulfides, which leads to α-thioimidoyl radicals that are less prone to undergo the C−S bond fragmentation (Scheme 224, eq b).489 Small amounts (5− 10%) of byproducts resulting from the addition of the arenethiyl radical formed via a photo-Fries rearrangement have also been observed.489b

7. ADDITION ONTO THE CS BOND OF N-HYDROXYPYRIDINE-2-THIONES Thiohydroxamic acid derivatives are excellent radical traps for thiyl radicals, the addition taking place at the sulfur atom of the CS bond and resulting in the generation of a carboncentered radical. This property of thiyl radicals has been exploited in highly efficient Barton decarboxylation reactions. Because thiohydroxamic esters can be regarded as activated BX


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7.1.1. Reductive Decarboxylation. The reductive decarboxylation can be achieved from thiohydroxamic esters (prepared in a previous step or formed directly in situ) in the presence of tert-butanethiol in toluene under thermal or photochemical activation (Scheme 226, eqs a,b).490 Garner and co-workers developed the thiouronium hexafluorophosphate 403 as an alternative reagent for the preparation of sterically hindered thiohydroxamic esters. The reductive decarboxylation of the latter could be achieved in the presence of tert-dodecanethiol either under thermal of photochemical activation (Scheme 226, eq c).491 The method proved to be general, and it was applied to numerous thiohydroxamic esters, including amino acid derivatives,492 peptides,492b and sugars.491,493 Crich and coworkers took advantage of the preference for hydrogen atom abstraction from thiols by glycosyl-1-yl radicals with an axial delivery to set the β-configuration of glycosides.493a−c,494 For instance, acid 404 was successively treated with 405 to give the corresponding thiohydroxamic ester. Subsequent treatment with t-BuSH under white light irradiation led to the formation of β-mannoside 406 in 75% yield as a single diastereoisomer (Scheme 227, eq a). The method also proved successful with more complex disaccharides,493c,d as illustrated by the diastereoselective reductive decarboxylation leading to 407 (Scheme 227, eq b).493d Rychnovsky and co-workers observed conformational memory during the reductive decarboxylation of N-hydroxypyridine-2-thione ester 408.495 Upon irradiation in toluene at −78 °C in the presence of a source of hydrogen atom, tetrahydropyran 409 could be obtained with partial retention of configuration. The best results were obtained using a 1 M solution of thiophenol, with tetrahydropyran 409 being isolated in 92% yield and with a high level of enantiomeric purity (86.5% ee), while the transfer of chirality was far less efficient with the use of tert-butanethiol and tri-n-butyltin hydride, from which the hydrogen atom abstraction was significantly slower (Scheme 228). The concentration and the temperature are two key factors here for successful memory of chirality. The kinetics of radical heterolysis reaction of radicals containing β-leaving groups has been studied by Newcomb and co-workers for β-(methanesulfonyloxy)alkyl radical 411 (Scheme 229).496 The latter was obtained upon irradiation of N-hydroxypyridine-2-thione ester 410 with visible light at room temperature in the presence of thiophenol, which not only acts as a chain carrier reagent by promoting the decarboxylation of 410 and trapping the resulting carbon-centered radical 411, but also reacts via electron transfer with vinyl radical cation 412 resulting from the heterolysis of radical 411. Radical cation 412 can either undergo 5-exo-trig cyclization to eventually give cyclic compounds, or react with thiophenol via electron transfer to give the noncyclized diene (Scheme 229). Barton and Crich extended the scope of decarboxylation reactions using thiohydroxamic derivatives to include alcohols.497 Reductive deoxygenation of tertiary alcohols can be achieved via their mixed oxalate esters with N-hydroxypyridine2-thione. Tertiary alcohols such as 413 are treated first with oxalyl chloride to give the corresponding half acyl chloride 414, then with thiohydroxamic acid (or the corresponding sodium salt) in the presence of 4-dimethylaminopyridine (DMAP) and tert-butanethiol in refluxing benzene. Upon heating in the presence of a thiol, the mixed oxalate ester 416 undergoes two (consecutive or concerted) decarboxylation reactions to give a tertiary alkyl radical 417, which then abstracts a hydrogen atom

esters, the best results are generally obtained with sterically hindered and thus poorly nucleophilic thiols such as tertbutanethiol or tert-dodecanethiol, for which the competing acylation reaction can be limited. Not only carbon-centered radicals but also nitrogen-centered radicals can be produced by this methodology, and these have been found to participate in carbon−carbon and carbon−nitrogen bond-forming reactions. Both intra- and intermolecular trapping of the radical intermediates produced in these decarboxylation processes have been achieved, but the latter generally requires the use of a large excess of the radical trap. In both cases, the trapping reaction must compete favorably first with the fast intermolecular hydrogen atom abstraction from the thiol. A second limitation in the case of reactions between carboncentered radicals generated by this approach and external radical traps is the competing addition of the carbon-centered radical onto the thiohydroxamic acid derivatives (vide infra).490 N-Alkoxypyridine-2-thiones proved to be suitable for the thiyl radical-mediated generation of oxygen-centered radicals. These aspects will be discussed in the following section. 7.1. Generation of Carbon-Centered Radicals

In contrast to the abstraction reactions from alkyl halides and chalcogenides, from which the halogen or chalcogen atom cannot be abstracted directly by a thiyl radical and requires the use of a silane (see sections 8.2.4 and 8.2.6), decarboxylation reactions involving the addition of thiyl radicals onto the CS bond of N-hydroxypyridine-2-thione derivatives allow for the thiyl radical to act as a chain carrier. As depicted in Scheme 225, Scheme 225

the addition of a thiyl radical onto the CS bond of thiohydroxamic ester 397 generates radical 398, which undergoes fragmentation by cleavage of the weak nitrogen− oxygen bond to give carboxyl radical 399 and mixed disulfide 400. Carbon-centered radical 401 generated during the decarboxylation process can then either abstract a hydrogen atom from the thiol or engage further in carbon−carbon or carbon−heteroatom bond-forming processes. Alternatively, it can also react in a chain reaction process with thiohydroxamic ester 397 to furnish the addition product 402 and a carboncentered radical 401 (Scheme 225). BY


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Scheme 226

Scheme 227

Scheme 228

from the thiol to give the product 415 and a thiyl radical that sustains the radical chain (Scheme 230). In some cases, the use of more bulky thiols was required to limit the competitive addition of the thiol onto the half acyl chloride. More recently, reductive decarboxylations have been reported to proceed directly from the carboxylic acids by photogenerated cation radical of phenanthrene in the presence of a thiol. In this case, the role of the thiol is limited to the trapping of the carbon-centered radical, and the resulting thiyl radical is not involved in a chain reaction.498 7.1.2. Intramolecular Trapping. Thiohydroxamic esters represent a mild source of carbon-centered radicals, which can engage in cyclization reactions. For instance, Whiting and coworkers showed that thiohydroxamic esters of aryloxyacetic acid allowed the generation of aryloxymethyl radicals upon

irradiation with a tungsten lamp in refluxing benzene. These carbon-centered radicals could cyclize to give dihydrobenzofurans (Scheme 231, eq a) and chromanes (Scheme 231, eq b).499 In the case of precursor 418, the radical intermediate underwent cyclization in a 6-endo-trig mode, and the resulting radical was trapped by another molecule of 418. Thermal elimination of the S-pyridyl group led to dehydroisoroterone 419 (Scheme 231, eq c).499 In reductive decarboxylation reactions of bridged, bicyclic systems, competing intramolecular hydrogen atom abstractions have been observed. Winkler and co-workers reported that the reductive decarboxylation of trans-bridged Barton ester 423 in refluxing toluene in the presence of tert-butanethiol led to cisbicyclic structures. In rigorously degassed conditions, cisbridged ketone 424 was obtained, while cis-bridged alcohol 425 was obtained in the presence of oxygen (Scheme 232, eqs a,b).500 Both compounds result from the translocation of radical 426 obtained by decarboxylation of 423 to give tertiary BZ


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Scheme 229

Scheme 230

alkyl radical 427. Hydrogen atom abstraction from the thiol by carbon-centered radical 427 furnishes 424. Trapping with molecular oxygen leads eventually to alcohol 425, presumably via alkyl hydroperoxide 428 (Scheme 232, eq c). A rate constant of 6 × 106 s−1 (298 K) was estimated for the radical translocation. 7.1.3. Intermolecular Trapping. Carbon-centered radicals generated from thiohydroxamic esters can be trapped by oxygen to give hydroperoxides that can be further reduced into the corresponding alcohols.490b,501 The decarboxylative oxygenation reaction can be carried out in the presence of tertdodecanethiol under an atmosphere of air or oxygen. The best results were obtained with esters derived from N-hydroxy-4methyl-2-thiazolinethione, which proved to be more stable than those derived from N-hydroxypyridine-2-thione, both under radical and ionic conditions. By using triphenylphosphine as the reducing agent for the hydroperoxides, primary, secondary, and tertiary alcohols were obtained in good to high yields (Scheme 233).501 Decarboxylative chalcogenations can also be achieved from thiohydroxamic esters. In this case, the decarboxylation reaction is carried out at high temperature under neat conditions and in

the presence of a large excess (typically 30 equiv) of diphenyl disulfide (Scheme 234).502 Barton and co-workers developed a decarboxylative phosphorylation reaction that allows one to convert carboxylic acids into nor-dithiophosphonates.503 The reaction is based upon the decomposition of thiohydroxamic esters in the presence of triphenyltrithiophosphite P(SPh)3 430, which plays the role of a radical trap for alkyl radicals generated during the decarboxylation process and provides thiyl radicals that ensure the propagation of the radical chain (Scheme 235, eq a).503 Mixed anhydrides derived from a carboxylic acid and a thiohydroxamic acid such as 429 or N-hydroxypyridine-2thione were found to participate in this reaction. The best yields were obtained with carboxylic acids derivatives leading to primary alkyl radicals. Homolytic substitution at the phosphorus atom in P(SPh)3 430 by the alkyl radical 432 produced in the decarboxylation process generates the trivalent phosphorus species R−P(SPh)2 433 and a benzenethiyl radical, which sustains the radical chain. The addition of the thiyl radical onto the CS bond of thiohydroxamate esters 429 initiates the decarboxylation process leading to alkyl radical 432 and mixed disulfide 434. The latter reacts with R−P(SPh)2 433 to give pentavalent phosphorus species 435, which is hydrolyzed in the presence of water to give dithiophosphonate 431 (Scheme 235, eqs b−d). In some cases, competitive attack of the alkyl radical at the sulfur atom was observed, leading to alkylphenylsulfides. Similarly, carbon-centered radicals resulting from the decarboxylation step could be trapped with trisphenylthioantimony CA


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Scheme 231

Scheme 232

Scheme 233

Sb(SPh)3 to give the corresponding alcohols after oxidation and hydrolysis.504 The intermolecular formation of a new carbon−carbon bond is also feasible using thiyl radicals as the chain carrier. Under nonreducing conditions (i.e., by using the fragmentation method with allylsulfides), tertiary alcohols could be used, via their mixed oxalate esters with N-hydroxypyridine-2-thione, as sources of carbon-centered radicals. Trapping of the radicals resulting from the deoxygenation process with the allylsulfides gave the allylation products in moderate to good yields (Scheme 236).409b 7.2. Generation of Nitrogen-Centered Radicals

Nitrogen-centered radicals can be generated from N-chloroamines505 and N-phenylthio derivatives.506 Newcomb and coworkers developed N-hydroxypyridine-2-thione carbamates as sources of nitrogen-centered radicals.507 The required Nhydroxypyridine-2-thione carbamates can be obtained either from the corresponding amines or from carbamoyl chlorides.507a Aminyl radicals such as 437 can be generated from carbamates such as 436, upon heating (50 °C), in the presence

Scheme 234

CB


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Scheme 235

Scheme 237

such as 439 (Scheme 238), as well as perhydroindoles and pyrrolizidines.507b It is noteworthy that, under these reaction Scheme 238

Scheme 236 conditions, the addition of the thiyl radical onto the CS bond competes favorably with the addition onto the CC bond (see sections 2.3.1 and 2.4.3 for some rate constants for the addition processes onto CC and CS bonds). 7.3. Generation of Oxygen-Centered Radicals

The use of O-alkyl thiohydroxamates allows one to generate oxygen-centered radicals via the selective cleavage of the nitrogen−oxygen bond (Scheme 239). This approach has been developed on solid support. By loading a suitable thiohydroxamic derivative onto a polymer support, the generation of radicals in solution can be obtained without contamination sulfur-containing heterocycles. For instance, Giacomelli and co-workers have attached alcohols onto a Wang resin by means of an N-alkoxythiazole-2(3H)-

of tert-butanethiol and a substoichiometric quantity of AIBN as an initiator (Scheme 237). Hydrogen atom abstraction from the thiol gives the free amines, while addition onto a radical trap could possibly deliver new poducts. In contrast to carboncentered radicals generated from the related N-hydroxypyridine-2-thione esters, no competing addition of the aminyl radical formed after decarboxylation onto N-hydroxypyridine-2thione carbamates 436 has been observed. Although aminyl radical generated from N-hydroxypyridine2-thione carbamate 438 failed to cyclize onto CC bonds when tert-butanethiol was used as the chain carrier, the corresponding aminium cation radicals 440 formed by carrying out the reaction in the presence of an organic acid participated efficiently in 5-exo-trig cyclizations, giving access to pyrrolidines

Scheme 239

CC


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thione (Scheme 240).508 Upon irradiation with a tungsten lamp (200 W) in the presence of tert-butanethiol, O-alkyl

Scheme 242

Scheme 240

thiohydroxamate 441 could be converted into tetrahydrofuran 442. The latter was isolated free from sulfur-containing byproducts after simple filtration of the resin and evaporation of the solvent.

8. THIYL-MEDIATED HYDROGEN ATOM ABSTRACTION As was already discussed in section 2.2, the reaction of carboncentered radicals with thiols may be described as an equibrium. Indeed, thiyl radicals rapidly abstract hydrogen atoms from weak carbon−hydrogen bonds (Scheme 241). The carbonconditions, hydrogen abstraction from the α-hydroxy position by a tert-butoxyl radical (t-BuO•) occurs, generating a carboncentered radical that undergoes fragmentation to give ketone 444 (via enol 445) and a thiyl radical. The latter sustains the chain by abstracting a hydrogen atom from β-hydroxythioether 443 (Scheme 242).511 Reversible hydrogen-atom abstractions from α-alkoxy-C−H bonds offer the possibility to achieve epimerization of chiral centers. Roberts and co-workers developed a method to epimerize chiral centers adjacent to an ether-oxygen atom.50b,512 The epimerization could be carried out in octane or nonane at 120−150 °C in the presence of substoichiometric amounts of a thiol and 2,2-bis(tert-butylperoxy)butane (DBPB) as a radical initiator. Various thiols, including alkanethiols such as tert-dodecanethiol or silanethiols, proved to mediate the epimerization. The best results were obtained in most cases with silanethiols such as tri-tert-butoxysilanethiol (TBST), but the use of more electrophilic thiyl radicals derived from 2,4,6tris-(trifluoromethyl)thiophenol or pentafluorothiophenol was sometimes needed.50b,512a The choice of the thiol is of crucial importance because some alkanethiols proved to be totally ineffective in systems for which complete epimerization could be obtained using silanethiols.513 Under these reaction conditions, the products distribution reflects the thermodynamic equilibrium and can be predicted on the basis of the relative stability of the different isomers.512b Cyclic ketals derived from simple 1,2- and 1,3-diols (Scheme 243, eq a),512a as well as more complex carbohydrate-based systems (Scheme 243, eq b), were found to undergo clean epimerization, thus demonstrating that a high regioselectivity can be observed also in polyoxygenated systems. If an unsaturation is present in the molecule, cyclizations of unsaturated acetals and thioacetals can be achieved.514 For instance, dioxolanes and 1,3-dithianes such as 446 and 447 could be cyclized in high yields in octane at 125 °C by using small amounts of 2,2-bis(tert-butylperoxy)butane (DBPB) as a radical initiator and a silanethiol such as tri-tert-butoxysilanethiol or triphenylsilanethiol as polarity-reversal catalysts (Scheme 244, eqs a,b). High yields were also obtained at lower temperatures in the presence of dilauroyl peroxide

Scheme 241

centered radical can then be reduced back to the starting material by the thiol or engage in further transformations, hence displacing the equilibrium. The use of catalytic amounts of thiol to generate electron-rich radicals via thiyl radicalmediated hydrogen abstractions has been extensively studied by Roberts and co-workers, who generalized the concept of transforming an electrophilic radical into a nucleophilic one via a favorable hydrogen atom transfer under the term of “polarityreversal catalysis”.509 Carbon−hydrogen bonds and heteroatom−hydrogen bond have been found to be reactive in the presence of thiyl radicals. For instance, hydrogen abstractions from silanes by thiyl radicals proved to be useful to generate silyl radicals. More recently, thiyl radicals have been found to abstract hydrogen atoms from NHC−borane complexes, thus allowing the generation of boryl radicals. This chapter focuses mainly on the synthetic applications of the chemistry of thiyl radical as agents for hydrogen atom abstraction; the last section discusses the relevance of this process in biological systems.510 8.1. Generation of Carbon-Centered Radicals

Both enthalpic and electronic effects favor hydrogen atom transfer from C−H bond linked to heteroatoms, making alcohols and aliphatic amines reactive substrates toward electrophilic radicals in general. The reactivity of thiyl radicals follows the same trend, and most of the reported synthetic transformations rely on the generation of α-heteroatom radicals. 8.1.1. Hydrogen Atom Abstraction from CH−OR Positions. Already in the 1960s, desulfurization of βhydroxythioethers such as 443 to give ketones 444 was found to take place using only substoichiometric amounts (ca. 5 mol %) of tert-butyl peroxide (Scheme 242). Under these reaction CD


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Scheme 243

Scheme 245

Scheme 244

The proposed mechanism involves in the initial step a hydrogen atom abstraction at the acetal moiety of 452. The resulting carbon-centered radical undergoes β-fragmentation to give 453, which abstracts then a hydrogen atom from the thiol, leading to the deoxygenated product and renegerating the thiyl radical (Scheme 246). EPR studies carried out with tert-butoxyl Scheme 246

(DLP) or di-tert-butyl hyponitrite (TBHN). Under these conditions, hydrogen abstraction by the electrophilic thiyl radical takes place at the acetal or thioacetal C−H bond. The presence of a gem-diester or gem-dimethyl substitution proved to be crucial because acetals lacking this substitution failed to cyclized under these reaction conditions. No traces of cyclized products were isolated in the absence of thiol. When no other alternative route is available, carbon-centered radicals generated by hydrogen atom abstraction at an acetal position may undergo fragmentation. Secondary and tertiary alcohols protected as methoxymethyl (MOM) ethers can be deoxygenated in the presence of a thiol as polarity-reversal catalyst.515 For instance, methoxymethyl ether 449, derived from 2-methyl-2-adamantanol, led to 2-methyl-2-adamantane in 87% yield upon heating to reflux in octane in the presence of catalytic amounts of tri-tert-butoxysilanethiol and 2,2-di-tertbutylperoxybutane (Scheme 245, eq a). Deoxygenation of 450 under similar reaction conditions could be achieved in high yields and with a high level of stereoselectivity, the hydrogen abstraction from the silanethiol by the carbon-centered radical 451 resulting from the β-fragmentation taking place at the less hindered exo-face (Scheme 245, eq b). Depending on the structure of the alcohol, the best results were obtained from either of the corresponding methoxymethyl (MOM)-, pmethoxybenzyl (PMB)-, or amidomethyl groups (PYRM).515b

radicals to abstract hydrogen atoms from t-BuOCH2OCH3 showed that the β-fragmentation is a fast process with a rate constant of 3.8 × 107 s−1 (399 K).515a The scope of this methodology has been extended to include the regioselective deoxygenation of 1,2- and 1,3-diols via the corresponding cyclic benzylidene acetals.516 For instance, benzylidene acetal 454 was selectively converted into benzoate 455 upon heating in octane (140−145 °C, bath temperature) in the presence of substoichiometric amounts of tertdodecanethiol or tri-tert-butoxysilanethiol and 2,2-di-tertbutylperoxybutane (DBPB), with no traces of benzoate resulting from the cleavage of the other carbon−oxygen bond (Scheme 247, eq a).516a Depending on the substrates, moderate to excellent levels of regioselectivity could be obtained for the ring-opening of the benzylidene acetal moiety. The regioselective cleavage of the carbon−oxygen bond usually follows the relative stability of the carbon-centered radicals resulting from the β-fragmentation; however, a complete reversal of the regioselectivity has been observed in bicyclic systems,516a−c presumably as a result of bond angle strain effects in the transition state of the β-fragmentation.517 For instance, the CE


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Scheme 247

Scheme 248

rearrangement of 4,6-O-benzylidene acetal 456 using tri-tertbutoxysilanethiol [(t-BuO)3SiSH, TBST] as polarity-reversal catalyst led to benzoate 457 in 89% yield via the formation of a primary alkyl radical intermediate, with only traces amounts of 458 (Scheme 247, eq b).516a,b DFT calculations of activation energies for both modes of cleavage in acyclic as well as in strained systems allow to predict which of the two carbon− oxygen bonds will be cleaved,516b,c in agreement with the absolute rate constants for the fragmentation determined by EPR spectroscopy.518 The use of tri-iso-propylsilanethiol and di-tert-butylperoxide as a radical initiator gave the best results in most regioselective ring-opening reactions of fused-bicyclic benzylidene acetals, with the cleavage of the primary carbon− oxygen bonds being usually favored in trans-fused systems, while secondary carbon−oxygen bonds are preferentially cleaved in related cis-fused systems. In deoxygenation reactions of 1,2-O-benzylidene acetals, the process is complicated by the competitive 1,2-migration of the benzoate group (Surzur−Tanner rearrangement) in the resulting 2-benzoyloxyalkyl (Scheme 248, eq a).519 As a result, the overall regioselectivity does not depend only upon the selectivity of the fragmentation process. Roberts and coworkers showed that a low concentration of thiol (ca. 2 mol %) is sufficient to achieve complete and highly regioselective conversion of glycopyranose derivative 459 into 2-deoxybenzoate 460, whereas the reaction is less selective at higher concentration (Scheme 248, eq b).516d Using thiyl radicals generated from perfluorinated aryl disulfides such as bis(pentafluorophenyl) disulfide on related benzylidene systems, the carbon-centered radical resulting from hydrogen atom abstraction may be oxidized into the corresponding carbocation by electron transfer to the disulfide.520 Silyl ethers of allyl alcohols can be converted into the corresponding silyl enol ethers using a thiol as catalyst.50a The best results were obtained with the highly electrophilic pentafluorothiophenol as polarity-reversal catalyst, while other thiols gave only low yields, including those giving good results in hydrogen atom abstraction in the ether and acetal series. Primary (Scheme 249, eq a) and secondary (Scheme 249, eq b) allyl silyl ethers underwent isomerization into the more stable enol ethers. The latter were obtained as an E/Z mixture of isomers as a result of a thermodynamic equilibrium between the

Scheme 249

two isomers under these reaction conditions. Hydrogen abstraction from secondary allyl silyl ethers proved to be slightly more difficult to achieve, and higher temperatures were required to ensure high yields. This effect seems to be general because similar observations have also been reported in the allyl amine series (see section 8.1.2). Isomerization of allyl ethers by a related mechanism using diphenyl disulfones has been reported. In this case, the resulting enol ethers were hydrolyzed to give the corresponding deprotected alcohols.521 A similar process has recently been reported to account for the isomerization of allyl alkyl ethers into the corresponding enol ethers during thiol−ene polymerization.522 8.1.2. Hydrogen Atom Abstraction from CH−NR2 Bonds. In analogy to the previous examples, thiyl radicals have been found to abstract hydrogen atoms from the allylic position of allylamines. Surzur and co-workers reported that thiazolidines such as 463 could be obtained from N-allyl-2aminothiols 462 upon chemical or photochemical initiation (Scheme 250).185,523 To account for the formation of thiazolidine 463, besides the expected cyclic compounds 464 CF


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Scheme 250

Scheme 251

energy in allylic amines, as well as C−Hγ bond dissociation energy in enamines resulting from the CC bond migration.49b Enamines were found to be more stable than the parent allylic amines. Moreover, stereoelectronic effects also proved to play a role in the strength of the C−Hα bond, with the lowest energy conformers being stabilized by both the overlap between the nitrogen lone pair and the σ*C−H orbitals and the overlap between the πCC and the σ*C−H orbitals. Using computational methods, a rate constant of 9.7 × 107 M−1 s−1 at 298 K has been estimated for the hydrogen abstraction from N,N-dimethyl allyl amine by the p-toluenethiyl radical.49b As for allyl ethers, the proposed mechanism involves reversible hydrogen atom abstraction from the allylic position in 474 by the electrophilic thiyl radical to generate allylic radical 475. Hydrogen atom abstraction from the thiol leads to enamine 476 and subsequent addition of the thiol to the enamine gives the thioaminal 477, allowing for the equilibrium to be displaced toward the formation of enamines. Hydrolysis of thioaminal 477 upon acidic workup gives amine 478 (Scheme 252).49a,b

and 465 resulting from 6-exo and 7-exo-trig cyclization, respectively, the authors proposed a mechanism involving reversible intramolecular hydrogen atom abstraction from the allylic position by thiyl radical 466 to give allyl radical 467. The latter can then abstract a hydrogen atom from a thiol to form thiolenamine 468, which undergoes (ionic and/or radical) cyclization to give thiazolidine 463 (Scheme 250).185b Interestingly, no hydrogen atom abstraction took place with related compounds for which the nitrogen atom has been replaced by an oxygen or a sulfur atom, demonstrating a high chemoselectivity for these types of hydrogen atom transfers.182b Although the mechanistic proposal seems very plausible, no evidence of the intramolecular character of this hydrogen transfer was given at the time. More recently, Bertrand and co-workers developed an elegant and highly chemoselective deprotection of allyl amines.49a,b,524 The reaction proceeds efficiently in refluxing benzene with tertiary and secondary amines by using either stoichiometric or substoichiometric amounts of a thiol and AIBN as a radical initiator. Upon acidic workup, the thioaminals resulting from the addition of thiocresol onto the enamine intermediates release the corresponding deprotected secondary and primary amines. The best results were obtained with thiocresol, although other thiols such as methyl thioglycolate or n-octanethiol also gave satisfactory results. Amines bearing an electron-withdrawing group, such as carbamate derivatives, do not react under these reaction conditions.49a,b As was previously observed by Roberts and co-workers in the secondary allyl silyl ethers series,50a hydrogen atom abstraction from secondary allylamines proved to be more difficult than that from primary ones, allowing for the selective deprotection of primary allylamines in the presence of secondary allylic positions (scheme 251, eq a).49a,b On the other hand, allyl benzylamines such as 471 led mostly to degradation products, probably due to competitive hydrogen atom abstraction from the benzylic position (Scheme 251, eq b).49b Allylamines can be selectively cleaved in the presence of allyl ethers, as illustrated by the deprotection of 472 (Scheme 251, eq c).49b Density functional theory (DFT) calculations have been used to estimate the C−Hα bond dissociation

Scheme 252

The reversible hydrogen abstraction from the C−H bonds located at the α position of amines by thiyl radicals allows the racemization of optically enriched benzylic49c and aliphatic525 amines (Scheme 253, eq a,b). Racemization of benzyl amines could be achieved in refluxing benzene in the presence a thiol and a catalytic amount of AIBN as a radical initiator. The proper choice of the thiol proved to be crucial to ensure high yields and complete racemization for a selected chiral amine. Theoretical calculations of the bond dissociation energies for both the C−H and the S−H bonds involved in the process allowed the authors to quantify the enthalpic factors. Under the optimized reaction conditions, primary, secondary, and tertiary CG


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Scheme 253

Scheme 255

optically active amines underwent racemization within a few hours. As a result of the strengthening of the α-C−H bond by acylation of the nitrogen atom,12 acetylated derivatives were found to be unreactive under these reaction conditions (vide infra). In some cases, oxidative degradation, presumably via the oxidation of the α-amino carbon-centered radical into the corresponding iminium ion, can compete with the desired reaction. The authors demonstrated that hydrogen abstraction from the thiol has to be fast enough to compete favorably with the oxidation process, and, as a result, the use of catalytic amounts of thiol gives satisfactory results only with the best hydrogen donors (typically arenethiols). Racemization of aliphatic amines, which present a stronger C−H bond than benzylic amines, require the use of thiols having a stronger S− H. The use of thiols such as methyl thioglycolate or noctanethiol allows their racemization in refluxing benzene,525a or even at 30 °C upon irradiation in a quartz or Pyrex vessel (Scheme 253, eq b).525b The absence of thiol-mediated racemization of N-acetyl derivatives offers the opportunity to achieve dynamic kinetic resolution (DKR) of α-chiral amines. Gastaldi, Gil, Bertrand, and co-workers reported an elegant approach combining lipasecatalyzed enzymatic resolution and in situ thiyl-mediated racemization.526 The principle of this dynamic kinetic resultion is depicted in Scheme 254.

excesses (ee > 99%) (Scheme 255, eq a). Dynamic kinetic resolution of primary amines could also be achieved at lower temperatures upon photochemical irradiation.526d The corresponding (S)-amides were obtained by using alkaline protease instead of lipases.525b,526c Because these enzymes have a lower thermal stability than CAL-B, dynamic kinetic resolution had to be carried out in this case at temperatures below 40 °C. Moreover, the sensitivity of enzymes upon irradiation at 300 nm requires for the dynamic kinetic resolution to be carried out sequentially via a one-pot three-step sequence, thus limiting the yields in optically enriched amides.526b A more convenient procedure involves the use of AIBN upon irradiation at 350 nm to initiate the reaction, in combination with trifluoroethanethiol and N-octanoyl alanine trifluoroethyl ester as the acyl donor (Scheme 255, eq b).526c 8.1.3. Hydrogen Abstraction from Benzylic and Allylic Positions. As particularly activated positions, bisallylic hydrogen atoms also undergo hydrogen atom abstraction by thiyl radicals. The Studer group developed an elegant radical hydroamination reaction of alkenes based upon the use of amino-substituted cyclohexadienes as a source of nitrogencentered radicals.528For review on the use of 1,4-cyclohexadienes as precursors for C-, N-, and Si-centered radicals, see ref 529. Nitrogen-centered radicals are known to add efficiently to alkenes. However, hydrogen atom abstraction from the N−H bond by the carbon-centered radical resulting from the addition process is inefficient. Using the concept of polarity-reversal catalysis with thiols, this unfavorable reduction step can be replaced by the hydrogen atom abstraction from the thiol. The hydroamination reactions could be carried out in benzene (sealed tube, 140 °C) in the presence of substoichiometric amounts of thiophenol and di-tert-butyl peroxide as a radical initiator. Under these reaction conditions, hydroamination of electron-rich alkenes could be achieved in moderate to good yields (Scheme 256, eqs a,b).528b The use of Hantzsch dihydropyridine derivatives such as 483, which present a weak nitrogen−nitrogen bond, allowed the radical hydroamination reaction to be carried our under milder reaction conditions (Scheme 256, eq c).530 The mechanism of this radical hydroamination involves hydrogen abstraction from the bis-allylic position of 482 by the thiyl radical, followed by aromatization of the resulting cyclohexadienyl radical 484 with concomitant loss of nitrogen-centered radical 485. The latter adds onto the electron-rich alkene, thus leading to the carbon-centered radical 486, which

Scheme 254

Racemic amines such as 479 could be converted into the (R)-amides 481 by using the thermally stable lipase B from Candida antartica (CAL-B),527 in combination with an acyl donor and a thiol (1.2 equiv), in heptane at 80 °C in the presence of AIBN as a radical initiator. In this case, the best results were obtained with N,N-diethyl-2-sulfanylpropionamide 480 (Scheme 255, eq a).526a The commercially available polymer-supported lipase Novozym 435 could be used in this DKR process, and, under these conditions, racemic primary amines were converted into the corresponding enantiomerically enriched amides in moderate to high yields and enantiomeric CH


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thermal process can be dramatically increased in the presence of catalytic amounts (0.5 mol %) of a benzyl mercaptan (Scheme 258, eq a).532 α-Branched aldehydes undergo

Scheme 256

Scheme 258

abstracts a hydrogen atom from the thiol to give aminated product 487 and a thiyl radical that propagates the chain (Scheme 257). decarbonylation very efficiently under these conditions, whereas the loss of carbon monoxide through α-fragmentation of acyl radicals of n-aldehydes proved to be more difficult. Aryl thiols also promote the decarbonylation of aldehydes upon irradiation, by using benzophenone or acetophenone as sensitizers.533 In these decarbonylation reactions, the thiol acts as a reducing agent to trap the carbon-centered radical resulting from the decarbonylation, while the thiyl radical rapidly abstracts the hydrogen atom from the aldehyde to form the acyl radical (Scheme 258, eq b). The radical addition of aldehydes onto terminal olefins was first reported by Kharasch in the late 1950s.534 The addition was found to take place in the presence of acetyl peroxide as a radical initiator or, alternatively, upon visible light irradiation. Electron-poor alkenes also proved to be suitable acceptors, and radical cascades leading to cyclic compounds were disclosed.535 This radical chain mechanism involves hydrogen atom abstraction from the aldehyde to give acyl radical 488, which then adds onto the alkene.534 Carbon-centered radical 489 resulting from the addition abstracts a hydrogen atom from the aldehyde to give ketone 490 and a new acyl radical that propagates the chain (Scheme 259). As for decarbonylation reactions, the low ability of alkyl radicals to abstract hydrogen atom from C−H bonds makes this last step rather ineffective, limiting the overall efficiency of the process. Roberts and co-workers demonstrated that thiol catalysts dramatically enhanced the yields of this transformation.536 The effect is particularly striking in the case of the vinyl acetate derivative (Scheme 260, eq a), for which a particularly unfavorable hydrogen atom transfer between the corresponding α-acetoxy radical and the electron-rich C−H bond of the aldehyde is replaced by two rapid hydrogen atom transfers, fully illustrating the concept of polarity-reversal catalysis: the nucleophilic α-oxygenated radical is very rapidly reduced by the thiol (see section 2.2.1), while the electrophilic thiyl radical efficiently abstracts a hydrogen atom from the aldehyde. The best results were obtained with methyl thioglycolate in the case of electron-rich and neutral alkenes (Scheme 260, eqs a,b).

Scheme 257

8.1.4. Generation of Acyl Radicals. As a particularly electron-rich and weak C−H bond, the aldehydic hydrogen is very reactive toward electrophilic thiyl or alkoxyl radicals. The following section describes reported reactions involving hydrogen atom transfers from aldehydes to thiyl radicals, putting the emphasis on the role of the thiol/thiyl radical couple in the process. We direct the reader to a comprehensive review for further details on the chemistry of acyl radicals.54 The decarbonylation of aldehydes via a free-radical chain mechanism is a long-known reaction531 that involves the thermal decomposition (α-fragmentation) of an acyl radical intermediate to form an alkyl radical and liberate carbon monoxide. Because of the high activation energy for the abstraction of the hydrogen atom from the aldehyde by the alkyl radical resulting from the decarbonylation step, the radical chains are relatively short, and, as a result, the decarbonylation of aldehydes via a radical pathway requires relatively large amounts (10−30 mol %) of di-t-butyl peroxide. In the early 1950s, Waters and co-workers showed that the efficiency of the CI


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Scheme 259

Scheme 261

Scheme 260

radical 495 intermediate proceeds more slowly than the ring expansion under these conditions (Scheme 261, eq c).514 Tomioka and co-workers reported a study on the cyclization of acyl radicals generated from aldehydes using thiols as polarity-reversal catalysts.537 The authors showed that cyclizations onto internal electron-poor and electron-rich alkenes can be achieved in good to high yields in the presence of substoichiometric amounts of tert-dodecanethiol and 1,1′azobis(cyclohexanecarbonitrile) (V-40) or AIBN as radical initiators, depending on the solvent used. Interestingly, at relatively high concentrations (ca. 1 M in aldehyde) and/or in the presence of an excess of thiol, cyclizations leading to fivemembered rings could be achieved without ring expansion into the corresponding cyclohexanones (Scheme 262).

Electron-rich arenethiols such as thiophenol proved to be far less efficient in this case; arenethiols possessing strongly electron-withdrawing substituents such as in tris(trifluoromethyl)thiophenol gave satisfactory results. For the addition onto electron-poor alkenes, tert-dodecanethiol (TDT), tri-iso-propylsilanethiol (i-Pr3SiSH), and triphenylsilanethiol gave the best results (Scheme 260, eq c). The reaction proved to be limited to linear aldehydes because extensive decarbonylation was observed with α-branched aldehydes (vide supra). Aldehydes possessing a carbon−carbon double bond located in an appropriate position undergo cyclization under polarityreversal catalysis conditions. For instance, (S)-citronellal 491 underwent cyclization in dioxane at 60 °C in the presence of catalytic amounts of tri-iso-propylsilanethiol and TBHN as a radical initiator, affording cyclohexanone 492 in 75% yield (Scheme 261, eq a).536b In the thiol-promoted cyclization of 493 using tri-tert-butoxysilanethiol as polarity-reversal transfer catalyst and 2,2-di-tert-butylperoxybutane (DBPB) or dilauroy peroxide (DLP) as radical initiators at 125 or 80 °C, respectively, cyclohexanone 494 was preferentially formed (Scheme 261, eq b). The reduction of the cyclopentylcarbinyl

Scheme 262

Stolz and Enquist used the thiol-mediated intramolecular addition of aldehydes onto alkenes to achieve the formation of the five-membered A ring of (−)-cyanthiwigin F, a marine diterpenoid isolated from the marine sponge Myrmekioderma styx (Scheme 263, eq a).538 In this case, the ring expansion leading to a six-membered ring was not observed due to the particular tricyclic structure. Donner and Casana reported a CJ


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264, eq b). These silyl radicals add rapidly onto unsaturated systems, including alkenes, dithiocarbonates and azides, or abstract halogen atoms, leading eventually to a new radical that is reduced by the thiol (Scheme 264, eq c). Hydrogen atom abstraction from a silane by an alkylthiyl radical is an endothermic process; however, consumption of the resulting silyl radical by reaction with an alkene or any other radical acceptor will displace the equilibrium, thus allowing the overall process to be efficient in this case. For the reaction to be successful, competitive reactions involving the thiyl radical must be slower than the desired reaction involving the silyl radical (vide infra), because these processes would result in the disappearance of the catalyst. Silanethiols (e.g., (TMS)3Si−SH), just as alkanethiols, are excellent hydrogen atom donors toward alkyl radicals. The resulting thiyl radical then undergoes a rapid 1,2-shift of a trimethylsilyl group to form a new silyl radical that can react further (Scheme 265, eqs a,b).543

Scheme 263

Scheme 265

8.2.2. Hydrosilylation Reactions. Silyl radicals add easily onto alkenes: absolute rate constants for the addition of Et3Si• onto a variety of electron-poor and electron-rich alkenes have been measured by LFP and range from 105 to 109 M−1 s−1 at 300 K.544 Roberts and co-workers reported that thiols catalyze the addition of silanes onto alkenes. Hydrosilylation of alkenes could be achieved at 60 °C with trialkylsilanes such as Et3SiH using a substoichiometric amount of a thiol (e.g., tertdodecanethiol, methyl thioglycolate, or triphenylsilanethiol) as the catalyst and di-tert-butylhyponitrite (DTBHN) as a radical initiator (Scheme 266, eq a).545 Because the irreversible

formal synthesis of racemic frenolicin B based upon the cyclization of an acyl radical generated via a chemoselective hydrogen atom abstraction.539 The presence of an alkyl substituent at the benzylic position proved to be crucial to ensure good yields, presumably by preventing competitive hydrogen atom abstraction from the sterically hindred benzylic position by the bulky tertiary alkyl thiol (Scheme 263, eq b). This strategy was also successful for the preparation of the related pyranonaphthoquinones.539 Dioxaspirocyclic systems were obtained from hindered disubstituted β-alkoxyacrylates, albeit in moderate yields.540

Scheme 266

8.2. Generation of Silyl Radicals

8.2.1. General Trends. As compared to the very popular tris(trimethylsilyl)silane ((TMS)3SiH),541 which proved to be a very efficient chain-carrier reagent for many radical transformations, the more economical silanes such as triethylsilane proved to be rather inefficient. The reactivity of trialkylsilanes is strongly limited by the strength of the silicon−hydrogen bond, which precludes efficient hydrogen atom abstraction from the silane by carbon-centered radicals (Scheme 264, eq a).542 Roberts and co-workers showed that thiyl radicals are capable of abstracting the hydrogen atom from silanes, thus allowing the generation of silyl radicals under mild conditions (Scheme addition of the silyl radical to the CC bond must compete with the reversible addition of the thiyl radical, the best results are typically obtained by using an excess of silane (sometimes used as the solvent) and a slow addition of the thiol.545 The use of aryl silanes proved to be somewhat more efficient, the adducts being obtained in good to high yields with only a slight excess of silane (Scheme 266, eq b).546 Hydrogen atom abstraction from the silane by the thiyl radical generates a silicon-centered radical, which undergoes intermolecular addition onto the alkene to afford radical 496.

Scheme 264

CK


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The latter abstracts a hydrogen atom from the thiol to give the product of hydrosilylation and a thiyl radical that propagates the chain (Scheme 267).

Scheme 269

Scheme 267

Prochiral radical species such as 496 can be trapped by hydrogen atom abstraction from a homochiral thiol, thus offering an entry to the enantio-enriched series. Very encouraging results were obtained by the Roberts group in this challenging enantioselective version of the thiol-mediated hydrosilylation of alkenes. The best results reported (up to 95% ee)547 were obtained with carbohydrate-based thiols, such as tetra-O-acetyl derivatives of 1-thio-β-D-glucopyranose and 1thio-β-D-mannopyranose (Scheme 268).546−548 The desulfur-

conditions, the pure trans-isomer being isomerized into a 79:21 mixture of cis- and trans-502 in the presence of DTBHN and triphenylsilanethiol. Seven-membered rings could also be prepared via a 7-endo mode.549 Allyloxy silanes such as 497 having activated C−H bonds at the allylic position underwent competitive hydrogen atom abstraction at the allylic position when tert-dodecanethiol was used as a catalyst, and a higher chemoselectivity in favor of the hydrogen atom abstraction for the Si−H bond was observed using silanethiols such as triphenylsilanethiol (Ph3SiSH) or tri-iso-propylsilanethiol (iPr3SiSH). 8.2.3. Generalities on Reduction Reactions. Only few examples of reduction can be achieved via a radical chain mechanism using solely thiols because they are usually not efficient at propagating the radical chain due to the poor ability of thiyl radicals to abstract atoms except hydrogen ones. The more favorable case in this context is probably Barton’s decarboxylation reaction in which a thiyl radical propagates the chain by addition onto the thiocarbonyl group (see section 7).110,550 In association with a silane, thiols are effective catalysts to achieve dehalogenation reactions or reduction of azides into amines. As previously, for the reaction to be successful, any possible competitive reactions eventually resulting in the consumption of the thiol catalyst must be suppressed. This aspect is crucial when a carbon−carbon double (or triple) bond, on which thiyl radicals can add, is present on the substrate (vide infra). 8.2.4. Dehalogenation Reactions. Trialkylsilyl radicals (R3Si•) are significantly more reactive than tin-centered radicals in halogen atom transfer reactions from alkyl halides RX (X = Cl, Br, I). For instance, tert-butyl bromide and tert-butyl chloride react with Et3Si• with rate constants of 1.1 × 109 and 2.5 × 106 M−1 s−1 (298 K)551 versus 1.4 × 108 and 2.7 × 104 M−1 s−1 (298 K) with n-Bu3Sn•.552 Nevertheless, as was already mentioned, alkyl and aryl silanes are rather poor reducing agents for carbon-centered radicals, precluding efficient radical

Scheme 268

ization of the thiol catalyst by homolytic substitution at the sulfur atom, a process that would generate an achiral reducing agent R3SiSH, has been found not to compete with the addition onto the electron-rich alkenes under these reaction conditions. The authors suggested that these achiral reagents are likely to be formed once the alkene has totally been converted into the product of hydrosilylation.547,548 Intramolecular additions are also possible under similar reaction conditions. For instance, alkenyloxysilanes such as allyloxy silane 497 were found to undergo 5-endo-trig cyclization in hexane or dioxane at 60−65 °C in the presence of substoichiometric amounts of a thiol and di-tert-butyl hyponitrite (DTBHN) as a radical initiator (Scheme 269, eq a), while the homologous homoallyloxy silanes, such as 498 and 501, gave the 5-exo- or 6-endo-products depending upon the substitution at the CC bond (Scheme 269, eqs b,c).549 EPR spectroscopic studies showed that the cyclization of these silyl radical intermediates is a fast process, with rate constants for the cyclization estimated to be ≥106 s−1 (333 K).549 Interestingly, the hydrogen atom abstraction from the silanethiol was found to be reversible under these reaction CL


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chain reactions. The use of a silane in combination with a thiol as a catalyst allows for circumventing this limitation. Roberts and co-workers showed that the reduction of alkyl halides could be achieved in the presence of an excess of silane (typically 2−4 equiv), substoichiometric amounts of a thiol, and a radical initiator such as di-tert-butyl hyponitrite (DTBHN).553 Various thiols were found to mediate these reductions, including tertiary alkyl thiols such as tert-dodecanethiol or adamantane-1thiol, perfluoroalkanethiols RFSH, or silanethiols such as Ph3SiSH. Other radical initiators, such as dibenzoyl peroxide and bis(4-t-butylcyclohexyl)peroxydicarbonate, gave also good results, while AIBN proved to be totally ineffective to initiate the reaction. Excellent yields were obtained for the reduction of primary, secondary, and tertiary alkyl halides (X = I, Br, Cl) in the presence of trialkyl or triaryl silanes such as Et3SiH, iPr3SiH, or Ph3SiH (Scheme 270). The more hindered tri-

Scheme 271

Scheme 270

halogen atom from the substrate to form the carbon-centered radical 505, presumably at the interface of the two phases. Hydrogen abstraction from the thiol in the aqueous layer furnishes the reduced product and a thiyl radical that sustains the radical chain. Water-soluble organic azides may also be efficiently reduced using this protocol (see below).554 8.2.5. Barton McCombie Deoxygenation Reactions. As in dehalogenation reactions, thiols can promote the reduction of O-alkyl-S-methyl dithiocarbonates by simple trialkylsilanes. S-Methyl xanthates derived from primary and secondary alcohols can be reduced into the corresponding alkanes in good to high yields in the presence of a trialkylsilane and catalytic amounts of tert-dodecanethiol and the appropriate radical initiator (Scheme 272).553b,555 In somes cases, the Scheme 272

isopropylsilane presents the advantage that the corresponding trialkylhalosilane 503 generated during the process is less prone to catalyze undesired side reactions of acid-sensitive substrates due to its bulkiness. With tris(trimethylsilyl)silane (Me3Si)3SiH, which possesses a Si−H bond weaker than that of trialkylsilanes, no thiyl radical is usually needed to form the silicon-centered radical, and classical modes of initiation with initiator such as AIBN can be used in most cases. However, Chatgilialoglu and co-workers demonstrated that the reduction “on water” of water-soluble alkyl and aryl halides with (Me3Si)3SiH could be dramatically accelerated in the presence of a small amount of the amphiphilic 2-mercaptoethanol (HOCH2CH2SH) (Scheme 271, eqs a,b).554 Whereas the reduction of water-insoluble substrates occurs in high yields in refluxing water in the presence of 1,1′-azobiscyclohexane-1-carbonitrile (ACCN) alone, the use of 2-mercaptoethanol proved to be crucial to obtain high yields with water-soluble substrates. In this case, both the thiol and the thiyl radical are believed to migrate between water and the lipophilic dispersion of the silane. In the lipophilic phase, thiyl radical 504 abstracts the hydrogen atom from the silane, and the resulting silyl radical then abstracts the

reduction occurred in high yields even in the absence of thiol, presumably thanks to thiol-containing byproducts, which may act as good hydrogen atom donors and catalyze the formation of silyl radicals. 8.2.6. Reductive Alkylations. Roberts and co-workers developed a radical-chain reductive alkylation of alkenes based CM


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upon the thiol-mediated hydrogen atom abstraction from silanes.547,556 For this approach to be successful, the formation of silyl radical 507 via hydrogen atom abstraction by the thiyl radical from silane 506 must compete favorably with the reversible addition of the thiyl radical onto the alkene (Scheme 273). Moreover, the halogen atom abstraction by the silyl

Scheme 275

Scheme 273 due to their reaction with the silyl radical and for alkyl azides, which gave only moderate yields under the same reaction conditions. The reduction of aryl azides may also be achieved by using the related n-Bu3GeH/PhSH system, but lower yields are generally obtained due to the formation of significant amounts of 2-germanylated anilines as byproducts.558 The proposed reaction mechanism involves hydrogen atom abstraction from the silane by the thiyl radical, followed by addition of the resulting silyl radical onto the azido group in 510, at either the internal or the terminal position. The resulting 1,3- or 3,3-silyltriazenyl radical 512 then undergoes extrusion of nitrogen to give the corresponding N-silylarylaminyl radical 513. The latter eventually abstracts a hydrogen atom from the thiol to yield silylaniline 514 and a thiyl radical that propagates the chain. Upon aqueous workup, desilylation of silylaniline 514 liberates aniline 511 (Scheme 276). radical leading to carbon-centered radical 508 needs to be faster than the irreversible addition of the silyl radical onto the alkene (vide supra). Finally, the addition of carbon-centered radical 508 onto the alkene leading to 509 must be faster than hydrogen atom abstraction from the thiol catalyst. As a result, the reaction is limited to the addition of electrophilic radicals onto electron-rich alkenes. These conditions can be fulfilled by using a combination of a trialkyl or triaryl silane, a thiol (typically methyl thioglycolate or triphenylsilanethiol), and a radical initiator to initiate the addition of electrophilic radicals onto a variety of electron-rich alkenes.556b Moderate enantiomeric excesses (up to 72% ee) were obtained by replacing the achiral thiol by a carbohydratederived homochiral thiol (Scheme 274).556b

Scheme 276

Scheme 274

As for organic halides (see above), water-soluble alkyl and aryl azides may be reduced into the corresponding primary amines in refluxing water by using (Me3Si)3SiH in combination with the amphiphilic 2-mercaptoethanol and 1,1′-azobiscyclohexane-1-carbonitrile (ACCN) as a radical initiator (Scheme 277).554

8.2.7. Reduction of Alkyl and Aryl Azides. Minozzi, Nanni, Spagnolo, and co-workers have developed a method for the reduction of aromatic azides into the corresponding anilines based upon the ability of silyl radicals to add onto the azido group. By using Et3SiH (typically 2−4 equiv) as the reducing agent in toluene at 110 °C in the presence of catalytic amounts of tert-dodecanethiol and 1,1′-azobiscyclohexane-1-carbonitrile (ACCN) as the radical initiator, most ortho-, meta-, and parasubstituted aryl azides could be reduced efficiently, as illustrated by the reduction of azide 510 into aniline 511 (Scheme 275).557 These conditions, however, were less efficient for aryl azides possessing an iodo, bromo, or nitro substituent, probably

Scheme 277

CN


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8.2.8. Desulfurization Reactions. During the course of their studies on thiol-catalyzed hydrosilylation of alkenes, Roberts and co-workers observed the desulfurization of the catalyst via a homolytic substitution at the sulfur atom by a silyl radical. For instance, desulfurization of β-glucose thiol 515 was achieved in excellent yield in the presence of triphenylsilane and a catalytic amount of di-tert-butylhyponitrite (DTBHN) as a radical initiator (Scheme 278, eq a). In this reaction, the thiol

Scheme 279

Scheme 278

tion.567 As for trialkylsilanes, this limitation may be overcome by using NHC−boranes in combination with a thiol, the electrophilic thiyl radical efficiently reacting with the B−H bond of the electron-rich NHC−boranes to release the corresponding boryl radicals.565 These reactions can be carried out at room temperature or at higher temperatures in the presence of a thiol such as thiophenol or tert-dodecanethiol. Different modes of initiation proved to be effective, including Et3B/O2, thermal initiation with di-tert-butylhyponitrite (DTBHN), and photochemical initiation with di-tert-butyl peroxide (DTBP). Under these reaction conditions, simple dehalogenation (Scheme 280, eq a) and 5-exo-trig cyclizations (Scheme 280, eq b) have been achieved in good to high yields from alkyl and aryl halides by using nearly stoichiometric amounts of NHC−boranes.

serves as a catalyst for its own reduction (Scheme 278, eq b).548,559 In the presence of an alkene, this desulfurization process does not compete with the hydrosilylation of the double bond (see section 8.2.2). 8.3. Hydrogen Abstraction from B−H Bonds (NHC·BH3)

Scheme 280

At the end of the 1980s, Roberts and co-workers showed that phosphine−borane complexes such as n-Bu3P·BH3 and n-Bu3P· BH2Ph could act as reducing agents for carbon-centered radicals.560 Shortly later, it was found that the reduction of simple alkyl bromides by phosphine−boranes in refluxing cyclohexane gave slightly better yields when the reaction was carried out in the presence of a catalytic amount of a thiol. This led the authors to conclude that “these initial results are promising, but clearly more reactive borane hydrogen-donors and/or more effective catalysts need to be found before these agents can offer a viable alternative to the tin or silicon hydrides”.553b More recently, Curran, Lacôte, Fensterbank, Malacria, and co-workers demonstrated that N-heterocyclic carbene−boranes (NHC−boranes) partially fulfill these criteria.561 The complexation of the boron atom with a Nheterocyclic carbene (as with other Lewis bases) has been found to significantly decrease the bond dissociation energy of the B−H,562 and N-heterocyclic carbene boranes such as 516 proved to be suitable reagents to reduce xanthates 518 (Scheme 279).561,563,564 NHC−boryl radicals such as 517 were found to abstract halogen atoms efficiently, with rate constants >105 M−1 s−1,565 but the chain reaction suffers from the relatively low rate of hydrogen atom transfer from NHC−boranes to alkyl radicals ((1−8) × 104 M−1 s−1, 298 K).566 Accordingly, N-heterocyclic carbene boranes may be used to achieve dehalogenation reactions; however, this process proved to be limited to alkyl halides having electron-withdrawing groups at the α-posi-

8.4. Hydrogen Atom Transfer from Metal Hydrides

Thiyl radicals have been suggested to play a role in the hydroplatination of phenyl acetylene in the presence of pchlorothiophenol and AIBN under photochemical initiation. One may envisage a behavior similar to that observed in thiolcatalyzed hydrosilylation reactions.568 Similarly, hydrogen atom transfer from tin hydride by thiyl radicals may take place, the catalysis resulting in a faster reduction process particularly useful to prevent radical rearrangements.406c In general, thiyl radicals may be expected to abstract hydrogen atoms from any metal−hydrogen bond weaker than the S−H bond. CO


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8.5. Hydrogen Atom Abstraction in Biological Systems

Scheme 281

8.5.1. Ribonucleotide Reductases. Present in all cellular organisms, ribonucleotide reductases (RNRs) catalyze the deoxygenation of all four nucleotides into 2-deoxynucleotides by forming a nucleotide radical upon hydrogen atom abstraction by a protein thiyl radical. RNRs were the first radical enzymes to be discovered,569 and they have been the subject of intensive studies ever since. The considerable amount of work that has been devoted to the structure and mode of action of RNRs being beyond the scope of this Review, the following section mainly focuses on some chemical aspects of the deoxygenation process. The reader is directed to previous dedicated reviews on the subject for additional details.1,570 Three classes of RNRs are generally distinguished depending upon how the initial thiyl radical is generated.571 Isolated from E. coli by Reichard and co-workers in the early 1960s,572 the first described ribonucleotide reductase represents an archetypal example of class I RNRs that are present in all eukariotes, for example, mammalians cells. This enzyme consists of two homodimeric subunits: R1 contains the active sites and the allosteric effector binding site;573 R2 stores the one-electron oxidant on the form of a stable tyrosyl radical bound to a dinuclear iron center.574 Upon binding of a diphosphate nucleotide substrate, the reductive process is initiated by a longrange proton coupled electron transfer (PCET) between the tyrosyl radical in R2 and the cysteine residue Cys 439 in R1.575 The resulting thiyl radical can then abstract the 3′-hydrogen atom from the nucleotide 518 (Scheme 281).576 This first step is endothermic, the thermodynamic equilibrium thus favoring the thiyl radical (see section 2.2);577 however, the process is driven toward the formation of the α-keto radical 520 thanks to the rapid elimination of a water molecule from 519. The ionic elimination of water from α,β-dihydroxyl alkyl radical under neutral conditions is relatively slow,578 but acid catalysis through protonation of the hydroxyl leaving group or base catalysis via deprotonation of the α-hydroxyl radical considerably accelerates the process.576b Theoretical study suggested that both effects might be operative in RNRs through a sophisticated hydrogen-bonding network where the hydroxyl leaving group is bonded to Cys 225 while the essential carboxylate group of Glu 441deprotonates the ketyl radical.577,579 Although its exact role is difficult to investigate, the resulting water molecule probably remains in the binding pocket and may relay subsequent proton transfers.577 The αketo alkyl radical 520 is then reduced by the cysteine residue Cys 462, resulting in a disulfide radical anion by coupling of the corresponding thiyl radical with the neighboring thiolate anion of Cys 225. The redox potential of the disulfide radical anion/ disulfide couple is normally too low to inject an electron into a keto group, but this step is probably facilitated through an elegant proton coupled electron transfer mediated by the amine moiety of the asparagic Asn437 and the carboxylic group of the glutamic acid residue Glu441 that protonates the oxygen atom of the carbonyl group of 522, making the latter a better electron acceptor.576b Finally, the resulting 3′-radical in 522 abstracts a hydrogen atom from Cys 439 to afford the 4-deoxyribonucleotide 523 and regenerate the initial thiyl radical, which restores the tyrosyl radical in the R2 subunit through proton coupled electron transfer. To complete the catalytic cycle, the disulfide bridge between Cys 225 and Cys 462 is reduced back into two thiol groups via double electron-transfer to a thioredoxin cofactor, itself eventually reduced by NADH.580

The deoxygenation mechanism of class II RNRs is closely related: the active site contains the same residues as class I RNRs, but the initial generation of the thiyl radical is ensured by a neighboring adenosyl B12 that forms an adenosyl radical in a suitable position to generate the required cysteine thiyl radical upon hydrogen atom abstraction.1,570b Class III RNRs are found in anaerobic microorganisms and may be seen as a more archaic version of the enzyme. It also relies on the initial formation of cysteine thiyl radical to abstract the 3′ hydrogen atom of the ribonucleotide, but in this case the genuine reducing agent is a formate molecule.1,570b Despite the rather low degree of homology between the primary structures of the three class of RNRs, the similar modes of action and mechanisms led to the idea that they may have evolved from a common ancestor, the major changes having been possibly driven by the apparition of oxygen on Earth. If arising from a unique origin, the first RNR has probably been a fundamental aspect of the transition between a RNA world to the DNAbased life as we know it.2,581 8.5.2. Other Enzymatic Processes. Saturated hydrocarbons are difficult substrates to metabolize, especially for anaerobic organisms.582 The ability of thiyl radicals to abstract hydrogen atoms from unactivated C−H bonds may be used by enzymes to initiate the oxidative degradation of alkanes. For instance, betaproteobacterium “Aromatoleum” degradates n-hexane by using a cysteine thiyl radical to abstract a hydrogen atom from the 2-position.583 The produced 2-hexanyl radical CP


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can then add to a fumarate molecule located in the active site, the resulting alkyl radical then abstracting the hydrogen atom from the S−H bond of cysteine to furnish 3-carboxy-4-methyl octanoic acid. The involvement of a thiyl radical in the mechanism of pyruvate formate lyase has also been suggested, although the addition of the thiyl radical to the carbon atom of the carbonyl group of pyruvate is unprecedented.584 8.5.3. Oxidative Damage to DNA. Free-radical damage of DNA is a well-known process affecting biological tissue under conditions of oxidative stress. Thiols represent an important class of biological reductants that protect endogenous molecules from oxidative damage caused by, among others, hydroxyl radicals (HO•) and peroxyl radicals (ROO•). Although thiols and especially glutathione are generally seen as antioxidants, their critical role in the regulation of oxidative stress makes thiyl radicals omnipresent species in biological systems.585 Their high reactivity may lead to undesired hydrogen atom transfers or addition reactions, which partially account for the mutagenic effect of thiols.586 Although carbohydrate-derived radicals are generally “repaired” by hydrogen transfer from thiols, the reverse reaction, hydrogen abstraction by thiyl radicals from carbohydrates, may also occur. Schöneich and co-workers have shown that hydrogen atom abstractions by thiyl radicals derived from cysteine from various carbohydrates take place with rate constants around 2 × 104 M−1 s−1 at 25 °C.65 Although relatively slow as compared to other reactions of thiyl radicals in cells, this reaction may be relevant in the case of site-specific formations of thiyl radicals in the vicinity of DNA. Thiyl radicals are mostly derived from cysteine residues in living cells; however, they can also be formed from exogenous molecules, which may account for some of the biological activities of sulfur-containing natural products. For example, the 3,6-epidithiopiperazine-2,5-dione (ETP) family of natural products possesses a disulfur brigde prone to generate thiyl radicals upon cleavage (Figure 5).

Scheme 282

the rate of hydrogen atom transfer from model peptides to thiyl radicals. Such processes may occur intramolecularly in cysteinecontaining peptides, giving rise to carbon-centered radicals that can then undergo further oxidation.66b,d When reversible under the reaction conditions, the process may promote L-to-D conversions of amino acids.66c Intermolecularly, cysteine thiyl radicals have been shown to abstract hydrogen atoms from the backbone of model peptides at rate constants varying from 103 to 105 M−1 s−1,588 resulting in the formation of particularly stable captodative radicals.589 Glycine derivatives are the most reactive substrates as the presence of a side chain dramatically decreases the rate of hydrogen atom transfer from the tertiary α-amino-α-carbonyl C−H bond, probably due to steric hindrance. Nevertheless, hydrogen atom abstraction from the side chains may then take place at rate constants up to 105 M−1 s−1 for the β-position of serine at 37 °C.590 In any case, the formation of carbon-centered radicals represents a starting point for protein degradation, potentially leading to their fragmentation/inactivation.66a 8.5.5. Hydrogen Atom Abstraction from Unsaturated Fatty Acids. More activated positions, such as biallylic C−H bonds, proved to be far more reactive. Thiyl radicals represent potential sources of lipid peroxidation by abstracting a hydrogen atom from bisallylic C−H bonds in polyunsaturated fatty acids.591 Pentadienyl radicals have been observed using pulse irradiation of NO2-saturated solutions of cysteine in the presence of polyunsaturated fatty acids, such as linolenic (18:3), linoleic (18:2), or arachidonic (20:4) acids, with absolute rate constants for the hydrogen abstraction from the bisallylic positions lying in the range 106−107 M−1 s−1.591a The reaction being largely exothermic, these rate constants are considerably higher than those for the reverse (″repair″) reaction, supporting that the formation of pentadienyl radicals

Figure 5.

The fungal metabolite gliotoxin 525 has been shown to induce DNA cleavage in vitro,513 the mechanism of which possibly involves the formation of thiyl radical 526 from 525. The latter has been suggested to abstract the 4′-hydrogen atom from the ribose 527 followed by DNA strand cleavage through the rapid fragmentation of the 3′ phosphate residue to form a radical cation 528. (Scheme 282).120c,d,587 Recent kinetic measurements by the group of Schöneich have shown that the pseudo benzylic methyl group of thymine may also undergo hydrogen atom transfer to a thiyl radical, although as for carbohydrates, the rate constant appears low for this reaction to be significant for freely diffusing thiyl radicals (ca. 104 M−1 s−1 at 25 °C).68 8.5.4. Hydrogen Atom Abstraction from Amino Acid Derivatives. The same group has reported several studies on CQ


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Notes

via hydrogen abstraction by thiyl radicals is a process that contributes to membrane damage (Scheme 283). In the cases of cis-fatty acids, this reaction competes with the reversible addition of the thiyl radical to the CC double bond that promotes Z/E isomerization (see section 5.1).81c

The authors declare no competing financial interest. Biographies

Scheme 283

8.5.6. Hydrogen Atom/Electron Transfer from Other Antioxidants. Nevertheless, thiyl radicals may be trapped by other antioxidants before attacking C−H bonds from biologically relevant molecules, thus preventing oxidative damage. Thiyl radicals are rapidly reduced by ascorbate, which appears to be a major path of reactivity under physiological conditions.592 Similarly, phenol derivatives such as folic acid may also contribute to the reduction of thiyl radicals to thiols via hydrogen atom transfer.593

Fabrice Dénès was born in Paris (France) in 1975. He completed his undergraduate and postgraduate studies at the University Pierre et

9. CONCLUSION Thiyl radicals can be prepared under very mild conditions from the corresponding thiols and disulfides as well as by fragmentation processes. Besides their ease of preparation, their reactivity is remarkable, and they can trigger an unusually broad and diverse chemistry. Simple reactions such as the thiol−ene coupling reaction are particularly efficient and broadly applicable under very diverse reaction conditions including working in aqueous solvent. More complex processes such as thiol−olefin cooxidation are highly attractive due to the simplicity of the reagents involved in the process (a thiol and molecular oxygen). Addition of thiyl radicals to terminal alkynes is the simplest approach for the generation of alkenyl radicals from simple and easily available precursors. Similarly, reaction of thiyl radicals with isonitriles affords thioimidoyl radicals in a straightforward manner. Addition of thiyl radicals to the thiocarbonyl group of Barton esters provides an efficient entry to the generation of alkyl radicals. On the other hand, processes involving fragmentation of thiyl radicals are very useful for inter- and intramolecular allylation, alkenylation, and acylation of radicals. Finally, in a completely different register, thiyl radicals proved to be highly efficient for the activation of allylic and benzylic positions via hydrogen atom transfer processes. The mildness and selectivity of this approach is unique and allows a wide range of applications ranging from alkene isomerization to reduction of halides and related compounds. Very often, these processes based on the concept of polarity-reversal catalysis require only a catalytic amount of the thiol. This Review highlights the versatility of thiyl radicals for organic synthesis. The use of thiyl radicals offers abundant possibilities for further elaboration of molecular architectures. Indeed, in many reactions, the thiyl moiety remains in the product as a thioether that can be easily transformed into alkanes (desulfurization), alkenes (oxidation−elimination or oxidation−olefination), and aldehydes (oxidation−Pummerer reaction).

Marie Curie (Paris, France) and received his Ph.D. in 2002 under the supervision of Prof. J.-F. Normant and F. Chemla. He then joined the group of Prof. P. Renaud at the University of Bern (Switzerland) as a Postdoctoral Associate. In 2005, he moved to the University of Nantes (France) where he was appointed Assistant Professor in the group of Prof. J. Lebreton (laboratory CEISAM, group SYMBIOSE). His research interests include the development of synthetic methods based on organometallic or radical reactions.

Mark Pichowicz studied chemistry at the University of Nottingham, obtaining his Ph.D. in 2006, working in the laboratory of Professor Nigel S. Simpkins. His graduate research was focused on enolate chemistry of diketopiperazines and application toward the synthesis of the brevianamide family of natural products. He then undertook Postdoctoral studies at the Institute of Cancer Research, London, researching the development of inhibitors of the Wnt signaling pathway. In 2009 he joined the research group of Professor Philippe

AUTHOR INFORMATION

Renaud as a Postdoctoral Research Fellow in the field of organic free-

Corresponding Author

radical chemistry. He is currently working in the pharmaceutical sector

*E-mail: [email protected].

in the North West of England. CR


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Reactive Intermediates in Chemistry and Biology; Chatgilialoglu, C., Asmus, K.-D., Eds.; Plenum Press: New York, 1990. (d) Voronkov, M. G.; Deryagina, E. N. Russ. Chem. Rev. 1990, 59, 778. (5) (a) Dondoni, A. Angew. Chem., Int. Ed. 2008, 47, 8995. (b) Dondoni, A.; Marra, A. Chem. Soc. Rev. 2012, 41, 573. (c) Hoyle, C. E.; Lowe, A. B.; Bowman, C. N. Chem. Soc. Rev. 2010, 39, 1355. (d) Hoyle, C. E.; Bowman, C. N. Angew. Chem., Int. Ed. 2010, 49, 1540. (e) ten Brummelhuis, N.; Schlaad, H. In Encyclopedia of Radicals in Chemistry, Biology and Materials; Chatgilialoglu, C., Studer, A., Eds.; Wiley: Chichester, 2012; Vol. 4: Polymers and Materials. (6) (a) Massi, A.; Nanni, D. Org. Biomol. Chem. 2012, 10, 3791. (b) Wille, U. Chem. Rev. 2013, 113, 813. (7) Majumdar, K. C.; Debnath, P. Tetrahedron 2008, 64, 9799. (8) For a book chapter on the reaction kinetics of sulfur-centered radicals, see: Griller, D.; Martinho Simões, J. A. In Sulfur-Centered Reactive Intermediates in Chemistry and Biology; Chatgilialoglu, C., Asmus, K.-D., Eds.; Plenum Press: New York, 1990. (9) For a book chapter on the gas-phase chemistry of sulfur-centered radicals, see: Urbanski, S. P.; Wine, P. H. In S-Centered Radicals; Alfassi, Z. B., Ed.; John Wiley & Sons: Chichester, 1999. (10) Denisov, E. T.; Chatgilialoglu, C.; Shestakov, A.; Denisova, T. Int. J. Chem. Kinet. 2009, 41, 284. (11) For a detailed discussion of the S−X bond dissociation energies (BDE) of sulfur-containing molecules, see: Armstrong, D. A. In SCentered Radicals; Alfassi, Z. B., Ed.; John Wiley & Sons: Chichester, 1999. (12) Luo, Y.-R. Handbook of Bond Dissociation Energies in Organic Compounds; CRC Press: Boca Raton, FL, 2003. (13) Denisov, E. T.; Tumanov, V. E. Usp. Khim. 2005, 74, 905. (14) Pratt, D. A.; DiLabio, G. A.; Mulder, P.; Ingold, K. U. Acc. Chem. Res. 2004, 37, 334. (15) (a) Bordwell, F. G.; Zhang, X.-M.; Satish, A. V.; Cheng, J.-P. J. Am. Chem. Soc. 1994, 116, 6605. (b) Nau, W. M. J. Org. Chem. 1996, 61, 8312. (16) Mulder, P.; Mozenson, O.; Lin, S.; Bernardes, C. E. S.; Minas da Piedade, M. E.; Santos, A. F. L. O. M.; Ribeiro da Silva, M. A. V.; DiLabio, G. A.; Korth, H.-G.; Ingold, K. U. J. Phys. Chem. A 2006, 110, 9949. (17) Heidbrink, J. L.; Ramírez-Arizmendi, L. E.; Thoen, K. K.; Guler, L.; Kenttämaa, H. I. J. Phys. Chem. A 2001, 105, 7875. (18) Borges dos Santos, R. M.; Muralha, V. S. F.; Correia, C. F.; Guedes, R. C.; Costa Cabral, B. J.; Martinho Simões, J. A. J. Phys. Chem. A 2002, 106, 9883. (19) Ollivier, C.; Renaud, P. Chem. Rev. 2001, 101, 3415. (20) Nguyen, V.-H.; Nishino, H.; Kajikawa, S.; Kurosawa, K. Tetrahedron 1998, 54, 11445. (21) Misra, H. P. J. Biol. Chem. 1974, 249, 2151. (22) Curran, D. P.; Martin-Esker, A. A.; Ko, S. B.; Newcomb, M. J. Org. Chem. 1993, 58, 4691. (23) Hoffman, M. Z.; Hayon, E. J. Am. Chem. Soc. 1972, 94, 7950. (24) Amaral, G. A.; Ausfelder, F.; Izquierdo, J. G.; Rubio-Lago, L.; Bañares, L. J. Chem. Phys. 2007, 126, 024301. (25) One should remember that the highly reactive hydrogen atom is also formed in this process: Pryor, W. A.; Stanley, J. P. J. Am. Chem. Soc. 1971, 93, 1412. (26) Zepp, R. G.; Wagner, P. J. J. Chem. Soc., Chem. Commun. 1972, 167b. (27) Ito, O. Res. Chem. Intermed. 1995, 21, 69. (28) Armstrong, D. A.; Chipman, D. M. In S-Centered Radicals; Alfassi, Z. B., Ed.; John Wiley & Sons: Chichester, 1999. (29) Razskazovskii, Y. V.; Mel’nikov, M. Y. In S-Centered Radicals; Alfassi, Z. B., Ed.; John Wiley & Sons: Chichester, 1999. (30) Batchelor, S. N.; Kay, C. W. M.; McLauchlan, K. A.; Yeung, M. T. J. Phys. Chem. 1993, 97, 4570. (31) Rhodes, C. J.; Dintinger, T. C.; Hinds, C. S.; Morris, H.; Reid, I. D. Magn. Reson. Chem. 2000, 38, S49. (32) (a) Davies, M. J.; Forni, L. G.; Shuter, S. L. Chem.-Biol. Interact. 1987, 61, 177. (b) Potapenko, D. I.; Bagryanskaya, E. G.; Tsentalovich, Y. P.; Reznikov, V. A.; Clanton, T. L.; Khramtsov, V. V. J. Phys. Chem.

Guillaume Povie was born in Bretagne (France),and started to study chemistry in Rennes (France) before joining the university of Nantes (France) where he completed his undergraduate studies under the supervision of Dr. Fabrice Dénès and Prof. Jacques Lebreton. In 2008, he went to work in the laboratories of Prof. Philippe Renaud at the university of Bern (Switzerland). His Ph.D. work focused on the development of synthetic methodologies using phenols as hydrogen atom donors and on mechanistic studies of radical reactions involving organoboranes.

Philippe Renaud was born in Neuchâtel (Switzerland). After undergraduate study at the University of Neuchâtel, he continued his education at the ETH Zürich through the Ph.D. in 1986 under the supervision of Prof. D. Seebach. In 1987, he was a postdoctoral associate of Prof. M. A. Fox at the University of Texas at Austin. He started in 1988 an independent research program at the University of Lausanne. He moved in 1993 to the University of Fribourg as an associate professor. Since 2001, he has been professor of organic chemistry at the University of Bern. His research interests include the development of synthetic methods with particular emphasis on radical reactions and the synthesis of alkaloids and other biologically active compounds.

REFERENCES (1) Kolberg, M.; Strand, K. R.; Graff, P.; Andersson, K. K. Biochim. Biophys. Acta 2004, 1699, 1. (2) Torrents, E.; Aloy, P.; Gibert, I.; Rodríguez-Trelles, F. J. Mol. Evol. 2002, 55, 138. (3) (a) Kooyman, E. C. Pure Appl. Chem. 1967, 15, 81. (b) Griesbaum, K. Angew. Chem., Int. Ed. Engl. 1970, 9, 273. (4) (a) Chatgilialoglu, C.; Guerra, M. In Supplement S: The Chemistry of Sulfur-Containing Functional Groups; Patai, S., Rappoport, Z., Eds.; John Wiley & Sons: Chichester, 1993. (b) Chatgilialoglu, C.; Bertrand, M. P.; Ferreri, C. In S-Centered Radicals; Alfassi, Z. B., Ed.; John Wiley & Sons: Chichester, 1999. (c) von Sonntag, C. In Sulfur-Centered CS


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DC


Thiyl radicals and induction of protein degradation.

Organic synthesis: Better chemistry through radicals.

Photoredox Mediated Nickel Catalyzed Cross-Coupling of Thiols With Aryl and Heteroaryl Iodides via Thiyl Radicals.

Reaction of vanadium(V) with thiols generates vanadium (IV) and thiyl radicals.

Oxenoids in organic synthesis.

Copper catalysis in organic synthesis.

Iron catalysis in organic synthesis.

Vinyl epoxides in organic synthesis.

Indenylmetal Catalysis in Organic Synthesis.

Enzymatic catalysis in organic synthesis.

Machine-Assisted Organic Synthesis.

Organic synthesis: The robo-chemist.

Design and synthesis of new stable fluorenyl-based radicals.

Reductive synthesis of aminal radicals for carbon-carbon bond formation.

Organic synthesis by quench reactions.

Organic chemistry. Streamlining amine synthesis.

Organic chemistry: Streamlining drug synthesis.

Enantioselective biotransformations of nitriles in organic synthesis.

Magnetically recoverable ruthenium catalysts in organic synthesis.

Influence of Electronic Effects on the Reactivity of Triazolylidene-Boryl Radicals: Consequences for the use of N-Heterocyclic Carbene Boranes in Organic and Polymer Synthesis.

The organic synthesis of unsaturated fatty acids.

Alkoxyallenes as building blocks for organic synthesis.

Identifying the factors that influence the reactivity of effluent organic matter with hydroxyl radicals.

Degradation of chlorotriazine pesticides by sulfate radicals and the influence of organic matter.