Thirty Years of (TMS)3SiH: A Milestone in Radical-Based

Review Cite This: Chem. Rev. 2018, 118, 6516−6572

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Thirty Years of (TMS)3SiH: A Milestone in Radical-Based Synthetic Chemistry Chryssostomos Chatgilialoglu,*,† Carla Ferreri,† Yannick Landais,‡ and Vitaliy I. Timokhin§ †

ISOF, Consiglio Nazionale delle Ricerche, Via P. Gobetti 101, 40129 Bologna, Italy University of Bordeaux, Institute of Molecular Sciences, UMR-CNRS 5255, 351 cours de la libération, 33405 Talence Cedex, France § Department of Biochemistry, University of Wisconsin-Madison, 1552 University Avenue, Madison, Wisconsin 53726, United States

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‡

ABSTRACT: This review is an update on tris(trimethylsilyl)silane, TTMSS, in organic chemistry, focusing on the advancements of the past decade. The overview includes a wide range of chemical processes and synthetic strategies under different experimental conditions, including functional group insertion and transformations, as well as preparation of complex molecules, natural products, polymers, surfaces, and new materials. These results reveal how TTMSS has matured over the past 30 years, and they further establish its value as a free radical reagent with widespread academic and industrial applications.

CONTENTS 1. Introduction 1.1. Historical Background 1.2. Peculiarities of (TMS)3SiH 2. Reduction of Functional Groups 2.1. Dehalogenation 2.1.1. Iodo-Derivatives 2.1.2. Bromo-Derivatives 2.1.3. Chloro-Derivatives 2.2. Reductive Removal of Chalcogen Groups 2.3. Deoxygenation of Alcohols 2.4. Reductive Decarboxylation 2.5. Reduction of Azide Groups 2.6. Desulfidation of Phosphine Sulfides 2.7. Miscellaneous Reactions 3. Beyond the Classical Reduction 4. Addition to Unsaturated Bonds 4.1. Hydrosilylation of Alkenes 4.2. Hydrosilylation of Alkynes 4.3. Hydrosilylation of Carbonyl Groups 4.4. Reaction with Molecular Oxygen 5. Intermolecular C−C Bond Formation Mediated by TTMSS 6. Intramolecular Consecutive Processes Mediated by TTMSS 6.1. Formation of Carbocycles 6.2. Formation of Heterocycles 6.2.1. Formation of Oxygen-Containing Heterocycles 6.2.2. Formation of Nitrogen-Containing Heterocycles © 2018 American Chemical Society

6.2.3. Formation of Boron-Containing Heterocycles 7. TTMSS As a Mediator of Rearrangements 7.1. Radical Rearrangements 7.2. Cascade Radical Processes 7.3. Miscellaneous Reactions 8. Applications of (TMS)3SiH in Polymerization 8.1. Photoinduced Free Radical Polymerization (FRP) 8.2. Silane Radical Atom Abstraction (SRAA) 8.3. Free Radical-Promoted Cationic Polymerization (FRPCP) 8.4. Photoredox Catalysis (PC) 9. Radical Chemistry of Poly(Hydrosilane)S 10. (TMS)3SiH in the Synthesis of Nanomaterials 10.1. Nanowires 10.2. Silicon Nanocrystal Surfaces 10.3. Miscellaneous 11. Radical Chemistry on Hydrogen-Terminated Silicon Surfaces 11.1. Chemical Similitude Studies of H−S(111) and H−Si(100)-2 × 1 Surfaces with (TMS)3SiH 11.2. Replacement of Hydrogen-Terminated Si(111) Surfaces with Heteroatom Moieties 11.3. Hydrosilylation of Silicon Surfaces 11.4. Oxidation of Hydrogen-Terminated Silicon Surfaces

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6542 Received: February 19, 2018 Published: June 25, 2018

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DOI: 10.1021/acs.chemrev.8b00109 Chem. Rev. 2018, 118, 6516−6572

Chemical Reviews

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Table 1. Kinetic Data for the Reactions of Carbon-Centered Radicals with (TMS)3SiH radical RCH2CH2• RCH2CH•(CH3) RCH2C•(CH3)2 C6H5• • RC (O) RfCF2CF2•

12. Conclusions and Outlook Author Information Corresponding Author ORCID Notes Biographies Dedication Abbreviations References

T (°C)

k (M−1 s−1)

log(A/M−1 s−1)

Ea (kJ/mol)

ref

25 25 25 20 23 30

3.8 × 10 1.4 × 105 2.6 × 105 ∼ 3 × 108 1.6 × 104 5.1 × 107

8.9 8.3 7.9

18.8 18.0 14.2

8.2

29.3

15 15 15 16 17 18

5

(d) the tolerability of aqueous conditions, enhancing its applicability to green chemical syntheses and processes, as well as to oxygen, which represent additional advantages over tin hydrides.6 The start and progress of (TMS)3SiH as radical-based reagent in organic synthesis have been presented from time to time in several reviews and books,1,5,7−11 and this review will give an overview of the chemical transformations reported so far, thus showing the well-known place in the reagent shelves and the scientific maturity reached after 30 years of its use. In nonradical reactions, numerous examples of (TMS)3Si group as a protecting group or bulky substituent have also been reported.12 We will present the various aspects of this silicon hydride recalling the fundamental mechanistic steps connected to the free radical chemical processes. The advancements of the past decade will be more focused, that not only reinforced TTMSS as the reagent of choice for its unmatchable convenience in organic synthetic processes in comparison to other radical and ionic procedures but also propelled these silicon-based compounds into a successful use in technological areas, such as polymers, surfaces, and new materials.

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1. INTRODUCTION 1.1. Historical Background

After 30 years from the first use of tris(trimethylsilyl)silane (TTMSS) in free radical chemistry,1 the scenario created by this reagent in organic synthesis represents a seminal example of strategic development, from the innate properties of a chemical element and its derivatives to the application for an ample variety of synthetic processes. The first papers in 1987−1988 furnished the thermodynamic and kinetic data thus showing the peculiar characteristics of the Si−H bond in the frame of the Group 14 hydrides,2,3 being at that time tributyltin hydride certainly the most known radical-based reagent in organic chemistry. The expertise in physical organic chemistry acquired by C. Chatgilialoglu as well as the collaboration with brilliant colleagues in K. U. Ingold’s laboratory were crucial for the consolidation of chemical basis on which the applications of the reagent to organic synthesis could be built-up. In the subsequent two decades, research from Chatgilialoglu’s and other groups showed the efficiency of radical chains sustained by tris(trimethylsilyl)silyl radical ((TMS)3Si•) for a variety of reductions, functional group transformations and bond creation, accompanied by the flexibility of procedures and of initiations by thermal and photolytic conditions. It was not immediately appreciated by the chemical community of those times, that (TMS)3SiH was an ideal reagent for “green” free radical chemistry, overcoming environmental and human toxicity issues of tin hydrides, with advantages of its safe frequent use in the laboratory and also for the preparation of noncontaminated pharmaceutical compounds to be biologically tested. By the intense activity of those years, other peculiarities of this silyl reagent were highlighted, such as (a) combination with other hydrogen donors, such as thiols, to modulate the occurrence of the reduction step, enlarging the applicability of the so-called polarity reversal catalysis introduced by B. P. Roberts;4 (b) favorable reactivity features that trigger molecular rearrangements of the substrates before the final reduction step, so that consecutive radical reactions could be strategically designed for complicated natural product syntheses;5 (c) typical bulkiness of the reagent with its three Me3Si-substituents on the silicon atom that strongly influence the approach to the substrate, thus conferring stereoselectivity to the free radical-mediated process;5

1.2. Peculiarities of (TMS)3SiH

The Si−H bond strength in silanes strongly depends on the nature of substituents. When the Me groups in Me3Si−H are progressively replaced by Me3Si groups, the Si−H bond is weakened by ∼17 kJ/mol per replacement. Thus, the Si−H bond dissociation enthalpy falls from 397.4 kJ/mol in Me3Si−H to just 351.5 kJ/mol in (TMS)3Si−H.7,13 The stability of silyl radical along the series (TMS)3Si• > (TMS)2Si(•)Me > (TMS)Si(•)Me2 > Me3Si• is due mainly to the spin delocalization onto the Si−C β-bond and in part to the relief of steric interaction among the TMS groups.7,14 Hydrogen atom abstraction from the Si−H bond of the silane is critical for radical reactions, as demonstrated in kinetic studies performed with a wide range of radicals. In Table 1, we collected the kinetic data available for the reactions of carbon-centered radicals with (TMS)3SiH. Rate constants for hydrogen abstraction by 1°-, 2°-, and 3°-alkyl radicals from (TMS)3SiH are roughly the same over the range of temperatures commonly used for liquid-phase reactions (due to compensation of entropy and enthalpy effects in the alkyl radicals). Phenyl and fluorinatedalkyl radicals in Table 1 are 2−3 orders of magnitude more reactive, while the acyl radical is at least 1 order of magnitude less reactive, than alkyl radicals. Kinetic data are also available for the reaction of nitrogen- and oxygen-centered radicals with (TMS)3SiH. The rate constant of dialkylaminyl radicals is similar to that of the analogous reaction of secondary alkyl radical (i.e., ∼ 3 × 105 M−1 s−1 at 76 °C).19 The rate constants of tert-butoxyl and cumylperoxyl radicals are 1.1 × 108 M−1 s−1 at 24 °C and 66 M−1 s−1 at 73 °C, respectively.20,21 Notably, molecular oxygen reacts spontaneously with (TMS)3SiH to give (TMS)3Si• and HOO• radicals (see section 4.4). 6517


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2. REDUCTION OF FUNCTIONAL GROUPS Most radical reactions of interest to synthetic chemists are chain processes that run under reductive conditions in organic solvents.23,24 Scheme 1a shows the reduction of a functional group X by (TMS)3SiH, where (TMS)3Si• radicals are generated by some initiation processes. The reduction chain propagated by removal of the X atom or group from the organic substrate (RX) by the (TMS)3Si• radical, via either a reactive intermediate or a transition state (shown in brackets). The radical R• then reacts with the silane giving the reduced product, RH, and a “fresh” (TMS)3Si• radicals to propagate the chain. The chain is terminated by radical−radical combination or disproportionation reactions. As far as the solvent for such transformation is concerned, it is worth underlining that (TMS)3SiH is neither soluble in water nor does it react with boiling water for several hours. These features encouraged its application to radical reactions in water.6,25 This is an important aspect dealing with environmental sustainability of chemical processes, especially for industrial applications. Thus, suspension of a water-insoluble substrate with (TMS)3SiH and the initiator 1,1′-azobis(cyclohexanecarbonitrile) (ACCN) in an aqueous medium at 100 °C under vigorous stirring gives the reduced substrates in good yields. For water-soluble substrates, the procedure was modified by adding a catalytic amount of amphiphilic 2mercaptoethanol that, when coupled to (TMS)3SiH, resulted in a very efficient method for removing various functional groups. In Scheme 1b, the 2-mercaptoethanol acts as a catalytic hydrogen atom donor since it is regenerated by reaction of the thiyl radical with the silane (cf. Figure 1).25

Figure 1 compares the rate constants for hydrogen abstraction from selected group 14 hydrides by primary alkyl radicals at 80

Figure 1. A graphic scale of rate constants for H-abstraction by primary alkyl radicals from various reducing systems at 80 °C.8

°C.8 Significantly, the rate constant for (TMS)3SiH is only ca. 5 times smaller than that of Bu3SnH. The kinetic effect of TMS groups on (TMS)3SiH reactivity can be seen in the silane where one TMS group is replaced by Me that leads to a 10-fold slower hydrogen-donor rate constant. Specific features of H atom donation allow the couple (TMS)3SiH/thiol to function as a free radical reducing system. The role of thiol is to modulate the H-donor reactivity of the system (cf. Scheme 1). With an alkyl thiol, (TMS)3SiH/RSH, the reduction rate constant increases to 0.9−8 × 107 M−1 s−1, while with an aryl thiol, (TMS)3SiH/ArSH, it rises to 0.75−1.5 × 108 M−1 s−1.22 Scheme 1. Mechanism of Reduction of a Functional Group (X = Atom or Group): (a) by (TMS)3SiH, Where the Structure in Brackets Represent a Transition State or a Radical Intermediate; (b) by (TMS)3SiH/RSH Couple, Where the Hydrogen Atom Donor to R• Radical Is the Thiol

2.1. Dehalogenation

In this section, the pure dehalogenation will be examined, whereas the dehalogenation that precedes the C−C bond forming will be treated in section 5. The reduction of alkyl halides to alkanes can be achieved by different methodologies, radical and nonradical ones,26 whereas the use of silyl radical-mediated reductions introduced several advantages of selectivity, flexibility, and tolerability, which are highlighted in the examples given in this section. The fundamental mechanistic steps of the silyl radicalmediated reduction are described in the Scheme 1, where the use of TTMSS in this type of reaction allowed chemo-, regio-, and stereoselectivities to be addressed, showing that this reagent is able to perform transformations that are not easily obtained by other reagents. 2.1.1. Iodo-Derivatives. Classical reaction conditions were used with a variety of substituted β-iodoethers 1 to afford clean deiodination products 2 in high yields (83−99%) (Scheme 2).27 The deiodination of 3 into the corresponding methyl-substituted product 4 proceeds smoothly in benzene at 60 °C.28 As mentioned before, one recently advanced feature concerned the feasibility of reactions in water.6 On this ground, it is not possible to substitute tris(trimethylsilyl)silane with tributyltin hydride. In aqueous systems, as shown by Chatgilialoglu’s group, a strategy has to be carried out that combines an amphiphilic thiol, such as 2-mercaptoethanol, and TTMSS as reducing agent to satisfactorily reduce water-soluble iodo-containing compounds, such as the nucleoside 5 and its analogous 2′-iodo-2′deoxyadenosine in excellent yields (Scheme 3).25 The deiodination process of bicyclopentane derivative 6 was reported using similar experimental conditions.29 Deiodination 6518


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kinetic study of the radical azidation with sulfonyl azides;33 in particular, the competition of secondary alkyl radical was used between H atom abstraction from TTMSS and azidation by sulfonyl azides. In the synthesis of derivatives of apramycin, an aminoglycosidic antibacterial compound, iodination, and reduction steps were used to eliminate the hydroxyl group in C-6′ position and study its importance for the binding site (Scheme 4). Indeed, the loss of the OH group in this position led to a loss greater than two-hundred times the specifically studied activity.34 The reaction conditions were smooth, by stirring the mixture in toluene at 65 °C for 3 h, giving a mixture of the deiodinated product 12 and its partially debenzylated congeners. The same research group effected more recently the reduction of another iodine-containing glycoside (Scheme 4);35 deiodination of 13 was best achieved using AIBN as initiation in benzene at 60 °C, which left the thioglycoside intact but resulted in partial removal of the carbamate by the silyl iodide generated as byproduct of the radical reaction. Further manipulation of the crude reaction mixture ultimately gave 14 in 78% overall yield for the three steps from iodide 13. It is worth noting that in other examples provided in this section, the resistance of the N-Boc protecting group under radical reducing conditions will be reported. 2.1.2. Bromo-Derivatives. Bromine reduction is an important step in the natural product synthesis, and the use of TTMSS brought an advantage for the ease and cleanliness of such reaction.26,36 An example is shown with the strategy for naturally occurring lactones, where the bromolactonization reaction was realized in an asymmetric version that affords the compounds with high enantiopurity, then leaving the task of the bromine elimination. The debromination of 15 is shown in Scheme 5, where the solid product 16 was recrystallized (heptane:EtOAc = 95:5), raising the enantiomeric excess to >99%.37 The aqueous version of debromination is shown in Scheme 5 with the bromo-substituted purine derivative 17, that is reduced in high yield under the conditions of amphiphilic thiol/ (TMS)3SiH couple at reflux, with catalytic ACCN initiation.25 For the conversion of bromides in structures where alcohol and different types of protecting groups are present, the silyl-based procedures become the method of choice as shown in the recent literature in the following cases (Scheme 6): for Ncarboxymethyl or N-benzyloxycarbonyl groups present in structure 1938 and structure 20,39 1,2-oxazines in structure 21,40 and galactose derivatives such as structure 22.41 For structure 21 in the anti-conformation, the TTMSS reduction gave excellent yields, competitive with the Ni-Raney reduction (yield 74%). Silyl radical-based debromination is also an alternative route to the classical hydride reduction for the transformation of epoxides into monoalcohols. In Scheme 7, these two alternative routes are shown, starting from the epoxide 23 to obtain the ascaroside derivative 25 during the synthesis of daumone, a pheromone which has control of the behaviors of plant parasites.42 In the synthesis of potential HIV integrase inhibitors inspired by polyphenolic compounds, the bromohydrin 26 shown in Scheme 7 is converted to the alcohol, without touching other acidsensitive functionalities, under standard reaction conditions in good yields (72−83%).43 The versatility of (TMS)3SiH reagent can be seen in the study of the debromination obtained by silyl radical not generated by the traditional use of azo-initiators. As a matter of fact, while debromination can be achieved by a variety of methods, free

Scheme 2. Radical Deiodination of a Variety of Compounds by Standard Reaction Conditions

Scheme 3. Radical Deiodination of a Variety of Compounds by (TMS)3SiH under Different Modes of Initiation and Experimental Conditions

of 7 was performed under irradiation with TTMSS in toluene and afforded the isobenzofuranone 8 in high yield and optical purity.30 In the study of different initiation conditions, the silanebased deiodination of 9 was also tested with the peroxyketal derivatives type 10 under conditions of acid-catalyzed activation to generate radicals at room temperature and below (Scheme 3).31 Irradiation by household fluorescent light bulbs or the presence of an air atmosphere is shown to initiate the desired reactions, thus providing highly practical reaction setups for dehalogenation of alkyl and aryl halides.32 The reduction of trans-4-phenylcyclohexyl iodide by TTMSS has been used in a 6519


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Scheme 4. Elimination of the Hydroxyl Group in C-6′ Position via Reduction of Iodo-Derivative (10 → 11) in Natural Product Synthesis and Deiodination of 12 Leaving Intact the Thioglycoside Group (The Iodine Substituent Is in Red Color)

Scheme 5. Debromination Procedure under Different Modes of Initiation and Experimental Conditions

Scheme 7. Bromohydrin Transformations in Natural Product Synthesis and in Medicinal Chemistry

Scheme 6. Substrates for Debromination with (TMS)3SiH (Yields of Reduction Products Are Reported in Parentheses)

the excitation by visible light of the Ir(III) and reduction to Ir(II) by 27, which is transformed into the corresponding amine radical cation, followed by debromination and generation of the radical that effects the H atom abstraction from the silyl reagent. The silyl radical initiation takes advantage of the presence of a minimum quantity of oxygen, and in fact, the reaction is totally inhibited by deep degassing. The advancements in photoredox catalysis gave rise to novel synthetic methodologies and to new reactivity trends connected with the catalyst characteristics, as summarized in a recent review.45 The debromination of 29 by (TMS)3SiH (Scheme 9) afforded a diastereomeric ratio 30:31 = 4:1 that is attributed to the bulkiness of the reducing agent. The preferential formation of 30 can be explained by reduction of the cyclic radical from the less hindered face anti to the two vicinal substituents (model 32).46 The transformation of gem-dibromides is involved in several strategies of diterpene synthesis, such as prevezols isolated from an alga found on the Greek island of Preveza in the Ionean Sea. Here the diastereoselective monodehalogenation 33 → 34 was realized under the condition of bulkiness of the silicon reagent, and indeed the desired reduction was obtained due to the favored

radical chemistry becomes more and more attractive for its selectivity and tolerance of functional groups, as well as mild reaction conditions. A successful example is reported by Devery and co-workers, using an alkyl or aryl bromide with a mix made of a compound for photoelectron transfer, such as [Ir(ppy)2(dtbbpy)]PF6 (28), an amine (diisopropylethylamine, 27), and TTMSS in equimolar amounts (Scheme 8).44 The optimized system is based on the mechanistic steps that includes 6520


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The polydebromination or polydehalogenation is an interesting step required in several synthetic schemes. In Scheme 11, the

Scheme 8. Light-Mediated Debromination of Alkyl or Aryl Bromides (Upper Part) And Possible Radical Initiation Steps (Lower Part)

Scheme 11. Mono- and Di-Debromination of Alkyl Bromides under Photoredox Conditions

photoredox conditions, as previously mentioned for single debromination (Scheme 8), were able either to mono- or didebrominate cyclopropane derivatives 36, affording 38 or 37, respectively. 44 The final step of polydebromination or polydehalogenation was required for the synthesis of polyhydrocarbons such as tritwistane (Scheme 12). The debromination Scheme 12. Di-Debromination Steps of Alkyl Dibromides in the Synthesis of Tritwistanes

Scheme 9. Diastereoselective Radical Reduction of Alkyl Bromide

of the dibromo-compounds 39 was achieved by (TMS)3SiH as the only condition where the reaction works.48 Multiple dehalogenation (41 → 42) is possible in a one-pot procedure by using the corresponding equivalent of reducing agent.49 Convenient synthesis of deuteriosilane (TMS)3SiD by direct H/D exchange mediated either by easily accessible Pt(0) complexes,50 iridium-pincer complexes,51 or cationic rhodium complexes52 have been recently reported. (TMS)3SiD is a good reagent for obtaining deuterated products. As an example, the synthesis of (2′R)-2′-deoxy[2′-2H]ribonucleoside derivative 44, starting from the corresponding bromide 43, was obtained with high diastereoselectivity and good yield (Scheme 13).53 The high stereoselectivity in this reaction is due to the transfer of deuterium atom from the less hindered side of the ring, whereas

approach of the reducing agent as shown in Scheme 10 (model 35).47 Scheme 10. Mono-Dehalogenation of Dibromide in the Synthesis of Prevezol C and Favored Intermediate for Diastereoselectivity

Scheme 13. Preparation of Deuterated Compounds Using (TMS)3SiD

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conditions of (TMS)3SiH/AIBN at temperatures 80−110 °C become the method of choice as shown in the following cases (Scheme 15): in glycoside chemistry, the removal of the chlorine

the use of THF-d8 (or 2,2,5,5,-tetramethyltetrahydrofuran) as solvent minimized hydrogen donation from the reaction medium. 2.1.3. Chloro-Derivatives. From the examples shown above, it is clear that the past decade has brought confirmation of the effectiveness of tris(trimethylsilyl)silane in dehalogenation procedures, as already reported by several groups with iodide and bromide compounds. Probably influenced by the fact that radical reductions of chlorides are generally not affected by tributyltin hydride, the application of the silyl radical reactivity toward chloride reduction was not immediately addressed, although first examples were provided by the Chatgilialoglu group.1 In the past decade, the silyl radical reduction of chloride substrates was to a greater extent addressed and interesting examples are available. The reduction of β-keto- and β-cyano-chlorohydrins (structures type 45) was examined using TTMSS and, after optimization, it was found that the chloromethine function could be reduced without competing formation of furans or side reactions involving other functional groups in the molecules (e.g., ketone, nitrile, and acetonide). In this way, β-hydroxy nitriles or β-hydroxy ketones 46a−46e were produced in good to excellent yield (Scheme 14).54,55 This strategy is adopted in the

Scheme 15. Selective Reduction of One Chloride Functionality (Yields of Dechlorination Product Are Reported in Parentheses)

Scheme 14. Key Steps of Dechlorination after Chlorine Atom Assistance in Chiral Aldol Reactions

in the anomeric position of 51,56 the removal of chlorine atom from the 2′-position of nucleoside 52,57 the removal of chlorine in piperidine derivatives such as structure 53,58 formation of a 3unsubstituted azetidinone from 54,59 and tolerance of epoxide functionality when the chloride reduction of 55 is effected in the synthesis of D-chiro-inositol derivatives.60 In the case of the chemoselective reduction of the chloride functionality reported for structure 56 in Scheme 16, the derivative 57 was obtained Scheme 16. Chemoselective Reduction of Chloride Functionality

under standard conditions in the presence of TTMSS, whereas the use of other methods resulted in an incomplete conversion to product or to unreacted starting material.61 Gem-dichloride compounds can be mono- or multipledechlorinated depending on the experimental conditions. A good example of monodechlorination shown in Scheme 17 as an Scheme 17. Reduction of Gem-Dichloride in a Diastereoselective Manner As Key Step in the Synthesis of Dactomelynes

synthesis of natural products (+)-solistatin (48) and (+)-dihydroxyashabushiketol (50).54 Radical reduction of the chloromethine function in 47 followed by a brief treatment of this mixture with p-TsOH afforded 48 in good yield and enantiomeric excess (94% ee). Reduction of the chloromethine function in 49 proceeded smoothly to provide 50 in excellent yield and optical purity (98% ee) (Scheme 14). For the reduction of chlorides in a variety of structures containing different types of protecting groups, the standard 6522


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intermediate step in the synthesis of natural products dactomelynes, where the gem-dichloride 58 afforded the reduced 59 in 98% yield.62 Moreover, the reduction at room temperature allowed the monochloride 59 to be obtained in a 13:1 diastereoselectivity. The preferential formation of 59 can be explained by reduction of the cyclic radical 60 from the lesshindered face. The reduction of gem-dichlorides 61a and 61b stopped cleanly at the monochloride derivatives, in quantitative yields as a diastereoisomeric mixture 62/63 = 1.7:1 for both cases (Scheme 18).63 The latter selectivity is likely due to the influence

Scheme 20. Desulfurization of Organic Sulfides

successfully separated by chromatography. 1,3-Dithiolane and related heterocycles are monoreduced by TTMSS in efficient radical chains.69 The compounds 68 and 70 gave very smooth reaction with the ring opening and subsequent H-abstraction from the silane, therefore leading to products 69 and 71, respectively, in good yields after isolation from flash chromatography (Scheme 21).70

Scheme 18. Reduction of Gem-Dichloride in Strained Rings

Scheme 21. Reduction of 1,3-Dithiane and 1,3-Dithiane-1,1dioxide

of the substituents on the rate of the cyclopropyl radical reduction and on the shielding of the two faces of the cyclopropyl ring.64 Bis-dechlorination product is reported in the synthesis of phospholipase inhibitors as shown in Scheme 18.65 Using 3 equiv of TTMSS, dechlorination of 64 to compound 65 proceeded smoothly and in good yield. The hydrogenation procedures are also important in material chemistry, for example when C−Cl bonds are converted into C− H bonds to ameliorate the characteristics of a material. This step has been recently reported for poly(vinylidene fluoride) (PVDF), a polymer with excellent pyroelectric, piezoelectric, and ferroelectric properties that are compromised by the chlorine substitution.66 Interestingly, TTMSS revealed an efficient reduction power toward this polymeric material. In this report, the authors highlighted that, for the first time, this procedure was attempted and showed advantages of efficiency, reaction rate, friendly conditions, and low sensitivity to oxygen and moisture, together with the perfect cleaning and metal-free conditions, simplifying the purification procedures and eliminating negative consequences on the material properties (Scheme 19).66

Similar reactions are observed with selenides. Scheme 22 shows the reductive removal of phenylseleno group from the selenide 72 and its anomeric isomer 73 in excellent yields.71 Analogous reactions were reported previously in phenylseleno derivatives of nucleosides.72 A method for efficient cleavage of resin-bound selenium and tellurium (74) using (TMS)3SiH has been reported (Scheme 22).73 The alkyl aryl ethers 75 were isolated by column chromatography in good yields and excellent purities. Apart from the molecular products, the reaction afforded resin-bound Se−Si(TMS)3 and Te−Si(TMS)3, characterized using high-resolution magic-angle spinning (HR−MAS) 2D 29Si/1H NMR spectroscopy. Phenyl selenoesters are reported to be reduced to corresponding aldehydes and/or alkanes when treated with (TMS)3SiH

Scheme 19. Efficient Dechlorination Procedure for Purification of Poly(Vinylidene Fluoride−trifluoroethylene)

Scheme 22. Deselenylation Reactions of Selenides

2.2. Reductive Removal of Chalcogen Groups

The removal of PhS group from n-C10H11−SPh by TTMSS is not an efficient step;67 it only occurs efficiently when it produces a stabilized carbon-centered radical. A recent example of desulfurization as expedient for stereochemical improvement in natural products was reported in the synthesis of an optically active fungal metabolite with antitumor properties.68 In fact, as shown in Scheme 20, the C-3 position of the skeleton presents the PhS group (66) and several reducing agents were tested. In the case of (TMS)3SiH, the ratio 67a/67b of 1:5 in 88% yield was found in favor of the desired stereoisomer that was then 6523


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under free-radical conditions (Scheme 23).17,74 The observed decrease in aldehyde formation along the series primary-
95%, 4 examples).25,63 These hydrosilylations in water were also initiated directly with light (low-pressure Hg lamp, 254 nm) in the absence of a chemical radical precursor (e.g., peroxide), where most of the light was absorbed by (TMS)3SiH.63 It has been suggested that all water-insoluble materials (substrate, reagents, and initiator) suspended in the aqueous medium can interact, due to the vigorous stirring that creates an efficient vortex and dispersion.

4.1. Hydrosilylation of Alkenes

The radical-based hydrosilylation of carbon−carbon double bonds by (TMS)3SiH is highly regioselective (anti-Markovnikov) and gives (TMS)3Si-substituted compounds in good to excellent yields. Hydrosilylation of monosubstituted olefins is an efficient process in the case of both electron-rich and electronpoor substituent affording alkylsilanes II (Scheme 51).140 The initially generated silyl radical adds to the double bond (in a reversible mode or not depending on the nature of alkene substituents) to give a radical adduct I, which then reacts with the silicon hydride and gives the addition product II, together with “fresh” (TMS)3Si• radicals to continue the chain. 6532


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For cis- or trans-disubstituted double bonds, hydrosilylation is still an efficient process, although slightly longer reaction times and one activating substituent are required. The addition of (TMS)3Si• radical to 1,2-dialkyl substituted olefins is reversible as it is shown for the interconversion of (E)- to (Z)-3-hexen-1-ol (177) in Scheme 53.146

Scheme 54. Visible-Light Mediated Hydrosilylation of Alkenes

Scheme 53. Catalytic Geometrical Isomerization of Compound 177 by (TMS)3Si• Radical

The use of photocatalysts revealed to be very important in enlarging the applicability of silyl radical-based processes as already shown for dehalogenation. Indeed, using an organophotocatalyst, Wu and co-workers recently reported an efficient visible-light mediated hydrosilylation of electron-poor and electron-rich olefins.147 The reaction shows a broad scope, being applied to a wide range of olefins bearing functional groups (ester, ketone, amide, epoxide, halide, and siloxane) and using common silanes (R3SiH, R2SiH2) including (TMS)3SiH (Scheme 54). Hydrosilylation occurs under mild conditions, using photocatalyst PC-A (4CzIPN) and quinuclidin-3-yl acetate or triisopropylsilylthiol as hydrogen-atom transfer catalysts. The reaction is believed to proceed through the quenching of PC-A* by the quinuclidine, leading to a highly electrophilic amine radical cation. The latter then abstracts the silane hydrogen, generating a silyl radical species which adds to the olefin to give a C-centered radical I. Single-electron-transfer from PC-A radical anion to I then leads to anion II which is trapped by a proton issued from the solvent as indicated by deuterium-labeling experiments. While this mechanism is viable for electron-poor olefins 178a prone to generate anion II, this is not the case for electron-rich analogues 178b. In this case, the authors had recourse to a polarity-reversal catalyst such as i-Pr3SiSH to act as a hydrogen-atom transfer agent. Under these conditions, the thiol is believed to play several roles: (1) it is thought to transfer its hydrogen to the C-centered radical I, resulting from the addition of the silyl radical onto the olefin; (2) the thiyl radical likely abstracts the hydrogen atom from the silane to generate the silyl radical, and finally (3) the ensuing thiyl radical is reduced by PC-A radical anion into a thiolate, which is eventually quenched by a proton, also regenerating PC-A. This strategy totally fulfills the requirement of atom and redox-economy and was further improved using continuous microflow system, which exhibits higher efficiency as compared to batch reactors with lower catalyst and HAT loading. Thiols can catalyze addition of (TMS)3SiH to alkenes. Scheme 55 shows that hydrosilylation of methylenelactone 180 using optically active thiols as catalysts, such as thioglucose tetraacetate 182 or the β-mannose thiol 183, occurs in excellent yields and good enantiomeric purities of 181 (cf. Scheme 1b for the reaction mechanism).148 Radical-mediated silyldesulfonylation of various vinyl sulfones 184 and (α-fluoro)vinyl sulfones 186 (R = alkyl or aryl) with (TMS)3SiH provides access to (E)- silanes 185 and 187, respectively (Scheme 56).149,150 These highly stereoselective reactions presumably occur via a radical addition followed by βscission with the ejection of the PhSO2• radical. They provide a stereochemical alternative to the hydrosilylation of alkynes with

Scheme 55. Enantioselective Hydrosilylation of Alkenes Using (TMS)3SiH/RSH Reducing System

(TMS)3SiH that affords mainly (Z)-vinyl silanes (vide infra). Upon oxidative treatment with hydrogen peroxide in basic aqueous solution, compounds 185 and 187 undergo Pdcatalyzed cross-couplings with aryl halides.149,150 The reactions of unsubstituted and 2-substituted allyl phenyl sulfides 188 (Z = H, Me, Cl, CN, CO2Et) with (TMS)3SiH give a facile entry to allyl tris(trimethylsilyl)silanes 189 in high yields (Scheme 56).151 In an analogous process, the unsubstituted and 2-substituted allyl phenyl sulfones afforded the same products in lower yields.151 In 6533


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intermediate I by the FeIII(t-BuO) species delivers the benzylic cation intermediate II, whose reaction with either an N or C nucleophile provides the corresponding desired product.152

Scheme 56. Various Reactions for Which the Key Step Is the Addition of (TMS)3Si• Radical to the C−C Double Bonds

4.2. Hydrosilylation of Alkynes

The radical-based hydrosilylation of monosubstituted acetylenes by (TMS)3SiH is highly regioselective and give terminal (TMS)3Si-substituted compounds in good yields (Scheme 58). Scheme 58. Hydrosilylation of Terminal Acetylenes by (TMS)3SiH

these reactions, the addition of (TMS)3Si• radical to the double bond is followed by β-scission with ejection of a thiyl or sulfonyl radical, thus affording the transposed double bond. Hydrogen abstraction from (TMS)3SiH by PhS• or PhSO2• radical completes the cycle of these chain reactions. Alternative pathways have been successfully applied to (TMS)3Si• radical-adduct of styrenes.152 In the presence of FeCl2 catalyst, di-tert-butyl peroxide and nucleophiles, a wide range of silicon-containing alkanes were obtained in good yields (191 and 192) from the substituted styrenes (190). Some examples are reported in Scheme 57 to illustrate the potential of these transformations, the nucleophiles being morpholine or indole. The proposed dual chain/catalytic mechanism is also illustrated in Scheme 57. Oxidation of the alkyl radical

The reaction can be initiated either by AIBN at 80 °C or by Et3B/ O2 at room temperature.140 High cis-stereoselectivity is observed for the reaction initiated by Et3B/O2 at room temperature (R = Bu, C6H11, Ph, or CO2Et) (193 → 194). Normally, (Z)-alkenes are formed because in the intermediate vinyl radical (σ-type) the bulky (TMS)3Si group hinders syn-attack. Only tert-butylacetylene afforded the (E)-alkene, which suggests a strained vinyl radical prior to hydrogen abstraction step. The hydrosilylation of terminal alkynes by (TMS)3SiH was also reported as an example for investigating radical reactions in solvents like tetrahydropyran143 or cyclopentyl methyl ether144 using 2,2′-azobis(2,4dimethylvaleronitrile) as radical initiator at 70 °C. A highly efficient air-initiated hydrosilylation of alkynes with (TMS)3SiH has been established under solvent-free conditions.145 In Scheme 58, the hydrosilylation of variously substituted acetylenes 195 is also shown under such conditions affording the silylated derivatives 196 in good yields and high cis-stereoselectivity. As in the hydrosilylation of alkenes, water-insoluble alkynes, suspended together with (TMS)3SiH and the radical initiator ACCN, in aqueous medium at 100 °C under vigorous stirring, can be transformed into (TMS)3Si-containing compounds in good yields.63 On the other hand, the hydrosilylation of watersoluble propiolic acid (197) is working well in the presence of amphiphilic thiol giving the Z-alkene 198 in 95% yield (Scheme 58).25 Scheme 59 summarizes the hydrosilylation of cyclohexylacetylene (199) under a variety of experimental conditions developed over more than two decades. It is noteworthy that molecular oxygen behaves as a radical initiator and that the solvent is not needed. Moreover, this water insoluble alkyne afforded the hydrosilylation product in water under oxygen

Scheme 57. Iron-Catalyzed Intermolecular 1,2Difunctionalization of Styrenes with (TMS)3SiH and Nucleophiles (Examples and Proposed Mechanism)

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Scheme 59. Hydrosilylation of Cyclohexylacetylene

Scheme 60. Radical Silylzincation of Ynamides and Heteroatom-Substituted Alkynes

initiation at room temperature in high yield and as a single geometrical isomer Z/E > 99:1. Radical addition of the (TMS)3Si group onto terminal ynamides has been approached recently by the work of Oestreich, Perez-Luna, et al. (Scheme 60).153 The silylzincation of ynamides 201a was found to be regioselective (β to nitrogen) and stereoselective, providing the Z-vinylsilane 202a, through a trans-addition of the silyl and zinc moieties across the triple bond. Protonation after silylzincation led to the Z-α,βdisubstituted enamide 202a, but transmetalation with copper also allowed further electrophilic trapping with primary, secondary allylic halides, propargyl bromides, as well as acyl chlorides to form useful adducts such as 202b (Scheme 60). The copper-mediated electrophilic substitution was found to occur with retention of the configuration. Vinylsilane 202b was further engaged in cross-coupling reactions after substitution of the (TMS)3Si group with a bromine atom. The strategy was later extended to sulfur, oxygen, and phosphorus-substituted alkynes 203a−203e (Scheme 61).154,155 The corresponding Z-α,βdisubstituted enamides 204a−204f were isolated with moderate to good yields, with stereoselectivities depending on the oxidation state at the sulfur center. For instance, high Z/E ratio was observed for alkynylthioether 204a, while no stereocontrol was observed for the sulfone analogue 204c. A similar trend was seen with phosphonate 204e. Good level of Z-stereocontrol was observed with sulfoxide 204b, albeit with modest yield, due to the formation in this case of a high amount (30%) of the carbozincation product. As above, the silylzincation product could be transmetalated with copper then alkylated with retention of the Z-stereochemistry of the olefin to give the allylated product 204f in moderate yield. These results contrast with previous carbometalation processes using Si−Cu156 or Si−Sn157 based reagents affording the complementary syn-selectivity. The trans-addition across the triple bond was rationalized invoking the decisive chelation of the Zn metal by the amide moiety. The mechanism was shown to proceed through a radical pathway as illustrated in Scheme 61. On the basis of pioneering studies by Apeloig et al.,126 it was proposed that reaction of R2Zn with oxygen would lead to the generation of an alkyl radical R•, which abstracts hydrogen from TTMSS to form the (TMS)3Si• radical precursor. The latter would then add selectively on the β-carbon of the ynamide, affording a vinyl radical I, which has two options: it may be reduced by TTMSS to form vinylsilane II or react with R2Zn through a homolytic substitution (SH2) process at zinc to form zinc-chelated species III, which leads to reduction under acidic conditions, and the R• radical that sustains the chain. The second

process is faster, and the stereoselectivity of the process is controlled by the Zn-chelation of the amide functional group. Manganese-catalyzed hydrosilylation of alkynes features diverse selectivities. In particular, the dinuclear catalyst Mn2(CO)10 and dilauroyl peroxide enabled the generation of Z products via radical pathways.158 4.3. Hydrosilylation of Carbonyl Groups

(TMS)3SiH undergoes synthetically useful addition to the carbonyl group, although the potentiality of these reactions are limited so far. Carbaldehyde 205 has been used as a probe for discrimination between radical and cationic mechanisms.159 Indeed ring-opening reaction depended on whether a radical or cationic intermediate develops at the carbonyl carbon, with consequent cleavage at C1−C2 or C1−C3 bond, respectively.160 The reaction of 205 with (TMS)3SiH under standard radical conditions afforded a mixture of (Z)- and (E)-alkene 206 from the regioselective ring-opening of the C1−C2 bond (Scheme 62). Water-insoluble carbonyl compounds are efficiently hydrosilylated in an aqueous medium, as shown in Scheme 62 for 6535


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Scheme 61. Possible Radical Mechanism for the transSilylzincation of Ynamides

Scheme 63. Insertion of Oxygen in TTMSS

an intramolecular mechanism, that both oxygens in the product molecule came from the same oxygen molecule. The mechanism of this unusual oxidation was examined in some detail. The absolute rate constant for the spontaneous reaction of (Me3Si)3SiH with O2 was determined to be kin ∼ 3.5 × 10−5 M−1 s−1 at 70 °C and quantum computing studies revealed the reaction coordinates.165,166 The reaction sequence of Scheme 64 is consistent with all observations.165,166 Thus, silyl Scheme 64. Proposed Reaction Mechanism for the Autoxidation of (TMS)3SiH Scheme 62. Hydrosilylation of Aldehydes and Ketones

4.4. Reaction with Molecular Oxygen

radical I adds to oxygen to form silyl peroxyl radical II, which then undergoes three unimolecular steps in the order: II → III → IV → V. The chain cycle is completed by hydrogen transfer from (Me3Si)3SiH to radical V affording oxididized product 211 and regenerating a silyl radical I to react with O2. There is good evidence to indicate that the formation of the dioxirane-like pentacoordinated silyl radical III is the rate-determining step (∼103 s−1 at 70 °C) of the three intramolecular steps. Oxygen can initiate new radical chains. Where this is the case, there is no need for an additional radical initiator. Indeed, a highly efficient air-initiated dehalogenation and hydrosilylation reactions with (TMS)3SiH as a reducing agent has been established under solvent-free conditions, and the oxidized product 211 does not interfere with radical reactions.

Left open to air at room temperature, (TMS)3SiH in bulk or solution phase undergoes a slow, spontaneous reaction with molecular oxygen to form the siloxane 211.163 The oxidation of (TMS)3SiH to 211 has also been achieved via an organocatalytic oxidation method.164 When (TMS)3SiH was treated with a mixture of 16O2 and 18O2 (Scheme 63), analysis of the crude products by mass spectrometry revealed similar label distributions in the products as in the reactants for both cases, indicating

5. INTERMOLECULAR C−C BOND FORMATION MEDIATED BY TTMSS TTMSS is a reliable reagent which is gradually replacing tin analogues for the generation of C-centered radicals.1,6−8,10,13 The slightly higher BDE of TTMSS as compared to Bu3SnH, however, allows consecutive reactions to take place before the silane donates its hydrogen atom to reduce the final radical.13

aldehyde 207.25 Likewise, ketone 4-tert-butyl-cyclohexanone 209 was hydrosilylated to mainly the trans ether 210, indicating that axial H-abstraction was favored (Scheme 62).161 (TMS)3SiCl has been used as a reagent to protect primary and secondary alcohols.162 Notably, the resulting silyl ethers are stable to the conditions normally used in organic synthesis to remove protecting silyl groups, but they can be deprotected by 254 nm photolysis in 62−95% yields. With the latter in mind, the hydrosilylation of aldehydes and ketones followed by photolysis affords a radical pathway that is formally equivalent to the ionic reduction of carbonyl moieties to the corresponding alcohols (see infra).

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This is used for instance in direct hydrosilylation of unsaturated systems, where the (TMS)3Si• radical adds onto the unsaturated moiety leading to a C-centered radical, which is eventually trapped by the silane, regenerating the (TMS)3Si• radical and providing the hydrosilylation product (see section 4). (TMS)3Si• radical may also be used to generate alkyl radical R• through abstraction of a X group (halogen, SePh, or xanthate) (Scheme 65), the addition of which onto an unsaturated system leads to a

Scheme 66. Diastereo- and Enantiocontrolled Alkyl Radical Addition onto Aldimines

Scheme 65. Possible Mechanism for TTMSS-Mediated C−C Bond Formation

Scheme 67. TTMSS-Mediated Perfluoroalkylation of Olefins new radical, which is finally reduced by the silane (TMS)3SiH. Neat addition of R−H onto an unsaturated bond thus results from such consecutive processes. As will be developed later in this section, other elementary steps (cyclization or rearrangement) may be incorporated between the addition of R• radical to the alkene and the final reduction of the adduct radical, enabling elaboration of complex structures through cascade radical processes.7 Carbon−carbon bond formation through intermolecular addition of alkyl and aryl radical species onto unsaturated bonds including olefins but also imines, oximes, and hydrazones CN bond has been extensively studied over the years.167 Substrate-controlled intermolecular addition to the imine derivatives has thus recently been described using sulfinylaldimines as prochiral substrates (Scheme 66).168 Generation of an alkyl radical using (TMS)3Si• radical was carried out in the presence of TTMSS and the Et3B/O2 couple. Activation of the imine functional group of compound 213 with TMSOTf led to the addition of the isopropyl radical, providing the sulfinylaminyl radical quenched by TTMSS. α-Branched amine 214 was thus obtained with reasonable yield and excellent diastereocontrol. Reagent-controlled addition of alkyl radical to arylimines 215 was also reported using binaphtol-derived chiral phosphoric acid catalyst 217. High level of enantiocontrol was obtained, independent of the electronic nature of the imine (Scheme 66).169 Addition of alkyl radical to activated and nonactivated olefins has been more thoroughly studied.167 Coupling of polyfluoroalkyl radicals to olefins (Scheme 67a) was found to be mediated by the (TMS)3Si• radical in water, following the radical pathway depicted in Scheme 65. Initiation of the process was carried out using oxygen or ACCN as the initiator, forming the silyl radical ready to abstract the halogen atom from RfX precursors 219a219d, thus generating the corresponding perfluoroalkyl radicals.170 Fast addition of the latter to 1-hexene 218 (known to occur with kadd ∼ 8 × 106 M−1 s−1), followed by fast reduction of the resulting C-centered radical with TTMSS, led to the desired perfluoroalkylated products 220a−220d in good yield

when RfI precursors 219a−219c were used. Modest to excellent yields were obtained both with unactivated and activated (acrylate and acrylonitrile) olefins. The fast addition of electrophilic radical Rf• to olefin, as compared to its reduction by TTMSS, is key to the success of this process. Competitive addition of (TMS)3Si• radical onto the olefin is not a problem here since it is reversible. Kinetic studies showed that the rate of the hydrogen transfer from TTMSS to Rf• radical was 4 times slower in water as compared to benzotrifluoride when used as a solvent. It is finally worth noting that no iodine atom transfer product was formed in these reactions, indicating a fast hydrogen transfer from TTMSS to the final C-centered radical. Good yields 6537


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Substrate-controlled intermolecular addition of alkyl radicals to double bond was reported to proceed with high cis-selectivity in lactams such as 228 (Scheme 69).175 TTMSS, acting as an

were obtained both with RfI and RfBr, when thermal initiation was performed using ACCN. Photoinduced radical perfluoroalkylation of activated olefins was also developed using TTMSS as a hydrogen atom donor.171 Perfluoroalkyl iodide is cleaved homolytically under UV-irradiation to generate the Rf• radical (Scheme 67b). Addition of the latter onto electron-poor olefins 221a−221b, followed by reduction with TTMSS occurred in good yields to provide perfluoroalkyl esters 222a−222b. This strategy was applied to the synthesis of enantiopure fluorinated α-amino acids, relying on the highly diastereoselective addition of these perfluoroalkyl radicals onto N-propanoylcamphorsultam precursors such as 223. The reaction led to adducts 224a−224d with high yield and diastereocontrol under these conditions (Scheme 67b). Photoredox-catalyzed difluoroalkylation of electron-deficient olefins 226 using fluoroalkylsulfonyl chlorides (RfSO2Cl) 225, has been described recently by Dolbier and co-workers,172 using TTMSS as both a hydrogen atom and electron donor (Scheme 68). The reaction proved efficient, leading to high yields of

Scheme 69. TTMSS-Mediated Diastereo- and Enantiocontrolled Addition of Alkyl Radicals onto Unsaturated Amides

Scheme 68. Photoredox-Catalyzed Difluoroalkylation of Electron-Deficient Olefins

hydrogen atom donor, was shown to approach anti relative to the resident R substituent, affording lactams 229a−229c in good yield and high cis-selectivity depending on the R size. Enantiocontrolled conjugate addition of alkyl radicals onto amides 230 has also been reported by Sibi and co-workers.176 Enantiotopic faces discrimination was performed using a Lewis acid Mg(NTf2)2 in the presence of a chiral bisoxazoline 231 (Scheme 69). TTMSS reacts as the hydrogen atom donor. Various alkyl groups could be transferred with excellent yields and a high level of enantiocontrol. The reaction being initiated with Et3B, a small amount of ethyl addition product was also formed. Thiomaleic anhydride 233 also served as a radical trap, as illustrated with the efficient TTMSS-mediated addition of alkyl radicals to 233, affording addition products 234 in good yields (Scheme 70).177

addition products 227 in the presence of α,β-unsaturated amides, ketones, sulfones, and esters. β-Substituent on the olefin led to lower yield as a result of steric hindrance. Various types of fluoroalkylated reagents 225 were studied, bearing methyl, phenyl, and also azido substituents (R1). Interestingly, while fluorinated radicals are usually considered as electrophilic, radicals issued from 225 were shown to be more reactive with the more electron-deficient olefins. Computational studies indicated that difluoroalkyl radicals might in fact be considered as nucleophilic due to transition state polarization effects. Only the trifluoromethyl radical is more electrophilic than the methyl radical. The mechanism of the process is believed to proceed through quenching of the Ir(III) catalyst, in its excited state, by the sulfonyl chloride, generating the fluoroalkyl radical after desulfonylation. Addition of the latter onto the olefin provides an electron-poor radical, which is trapped by TTMSS, affording the desired product along with the (TMS)3Si• radical. The latter then reduces the Ir(IV) catalyst back to its ground state, forming a silyl cation, eventually trapped by the chloride anion. An alternative pathway might also be considered, in which the formation of the RfSO2• radical would rely on the known fast abstraction of the chlorine atom from RSO2Cl by the (TMS)3Si• radical (k > 108 M−1 s−1).173,174 In this case, the Ir catalyst would only act as an initiator.

Scheme 70. TTMSS-Mediated Addition of Alkyl Radicals onto Thiomaleic Anhydride

Nucleophilic acyl radicals are known to add efficiently to electron-poor olefins. Following the general picture drawn in Scheme 65, acyl radicals generated from the corresponding acyl selenides (e.g., 235, Scheme 71) were effectively shown by Landais et al., to add to Baylis-Hillman adducts such as 236, with high levels of diastereocontrol after abstraction of the SePh group by (TMS)3Si• radical (Scheme 71).178 Higher diastereocontrol was observed with TTMSS as compared to Bu3SnH, as a result of an increase of steric hindrance with the former hydrogen atom donor. The syn relative configuration of the product 237 was 6538


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transfer from TTMSS, which eventually led to pyrrolidine 246 with high diastereocontrol (Scheme 71). Carboxylic acids 247 may also be considered as a viable source of acyl radicals, as illustrated by Yu, Zhu, and co-workers who recently devised an hydroacylation of olefins 248 using a photoredox strategy and TTMSS as an hydrogen source and reducing agent.181 The scope of the reaction was shown to be limited to acyl radicals from benzoic acids 247, styrenes, and electron-deficient olefins. The reaction is mediated by an Ir photocatalyst and visible-light (Scheme 72).

Scheme 71. TTMSS-Mediated Acyl Radical Addition to Baylis-Hillman Adducts

Scheme 72. Photoredox-Catalyzed Hydroacylation of Olefins

rationalized invoking transition state A, in which TTMSS approached anti relative to the large silyloxy group, with the small hydrogen eclipsing the ester group. Interestingly, the resulting adducts were then elaborated further into the corresponding 2,3,5-trisubstituted tetrahydrofurans (e.g., 239), after silyl ether deprotection, BF3-catalyzed formation of the acetal, and final reduction of the oxocarbenium ion, using again TTMSS. The latter proved to be superior, in terms of diastereocontrol, to Et3SiH generally used for these ionic reductions. The whole sequence starting from the Baylis-Hillman adduct 238 could be realized in a one-pot operation using TTMSS both for radical then ionic-mediated hydrogen atom transfers. This methodology was also extended to the addition of acyl radicals to cyclic αalkoxymethylene butyrolactone including 240, leading to the addition product 241 with excellent diastereocontrol. Product 241 was eventually elaborated further into (+)-No. 2106 A (242), a marine fungus secondary metabolite in 20% overall yield and 8 steps from commercially available D-xylose acetonide.179 An extension of this chemistry was finally performed to access 2,3,5-trisubstituted pyrrolidines and indolizidines starting from aza-Baylis-Hillman adducts 244.180 TTMSS-mediated acyl radical addition to 244 starting from acylselenide 243 led to the desired addition product 245 in good yield and moderate diastereocontrol. Addition of BF3·Et2O triggered the cyclization of 245 into a hemiaminal, followed by ionic hydrogen atom

The reaction starts with the combination of the benzoic acid and dimethyldicarbonate (DMDC), providing a mixed anhydride, which is an efficient oxidative quencher of the Ir photocatalyst, in its excited state. Decomposition of the radical anion, thus formed, provides the required acyl radical which then adds onto the olefin, forming radical intermediate I. Hydrogen atom transfer from TTMSS then furnishes the final product 249 along with the (TMS)3Si• radical. The latter may, as already mentioned above (Scheme 72), reduce Ir(IV) into Ir(III) to give a silylium ion likely trapped by a methanol source present in the medium. Acyl radicals are prone to decarbonylation, when the resulting radicals are somewhat stabilized. This was used on purpose by Inoue et al. to devise an efficient decarbonylative radical coupling between α-aminoacyl tellurides and enoates as well as activated oximes (Scheme 73).182 Decarbonylation is faster with acyl 6539


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Scheme 73. TTMSS-Mediated Decarbonylative Radical Coupling of α-Aminoacyl Tellurides

Scheme 74. TTMSS-Mediated Alkyl Radical Addition to Fluorinated Alkenes and Alkynes

from α-bromo esters 258 onto terminal alkynes was reported to provide the corresponding Z-alkenes 259 using copper catalysis and TTMSS as the most efficient hydrogen source (Scheme 74).185 Although the mechanism was not elucidated, addition of TEMPO or BHT was shown to preclude the reaction, indicating the occurrence of a radical process. Finally, aryl radicals, generated from aryl iodides such as 260 and (TMS)3Si• radical, may also be added intermolecularly to unsaturatated bonds including arenes.186 The reaction requires that an excess of the arene acceptor is present. Nondegassed solvents are used as to favor the oxidative rearomatization. The procedure is operationally simple but affords the desired biaryls 261 with modest regiocontrol when substituted arenes are used. Better results are observed for intramolecular processes. TTMSS is able to generate halomethyl radicals from CH2Cl2 or CH2Br2 both used as alkylating agents and solvents. Detrembleur and co-workers have used this strategy to prepare cobalt-acetylacetonate-CH2X precursors 262 (Scheme 75).187 The weak carbon−cobalt bond of this complex allows the release of the halomethyl radicals upon heating, which may then add to

tellurides 250 than the direct addition of the acyl radical onto the activated olefin. Abstraction of the PhTe group by the (TMS)3Si• radical thus led to the corresponding acyl radical I, which upon decarbonylation generated the desired α-amino carbon radical II, the addition of which onto methyl acrylate affords the amino ester 251 in generally good yield after final reduction by TTMSS. The methodology was also applied to the addition to oximes 252, affording aminoesters 253. An application of this methodology to the synthesis of naturally occurring manzacidin A was also reported (Scheme 73).182 The same group synthesized α-alkoxyacyl tellurides derived from D-tartaric acid that were utilized for stereoselective coupling reactions with electron-deficient double bonds.183 Treatment of the α-alkoxyacyl tellurides with Et3B/O2/TTMSS at room temperature promoted acyl radical formation and subsequent decarbonylation to form the corresponding α-alkoxy radicals, which add to various CC conjugated with electron-withdrawing groups. Benzaldehyde-ketyl radical generated through the reaction of benzaldehyde with (TMS)3Si• radical was shown to add efficiently to fluorinated esters such as 256 to afford trifluorobutanoic acid derivatives 257 with satisfying yield but low diastereoselectivity (Scheme 74).184 The reaction could be extended to several substituted benzaldehydes and arylketones. Alkyl aldehydes did not form the ketyl radical, and the reaction under these conditions led instead to the addition of the (TMS)3Si• radical to 256. Addition of alkyl radicals generated

Scheme 75. TTMSS-Mediated Formation of Halomethyl Radicals (X = Br or Cl)

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prostanoid precursor, in high yield, but as a mixture of four inseparable diastereomers in a 35:25:20:20 ratio.193 The 5-exo-dig radical cyclization onto triple bonds has also been documented. Kumamoto and co-workers thus studied the 5-exo-dig cyclization of the alkyl radical generated from selenide 271 using TTMSS as a mediator and hydrogen atom donor.194,195 Cyclization at low temperature occurred efficiently to give a mixture of four stereoisomers, in which the (Z)-syn-272 was largely predominant (Scheme 77).

activated olefins such as vinyl acetate to provide polyvinyl acetate polymers with controlled molar mass and polydispersity.

6. INTRAMOLECULAR CONSECUTIVE PROCESSES MEDIATED BY TTMSS 6.1. Formation of Carbocycles

TTMSS is a useful reagent to mediate radical cyclizations.188 The organosilane has relatively strong Si−H bond (as compared to Sn−H bond) and effectively allows the formation of C-centered radicals and their subsequent cyclizations instead of their direct reduction. The 5-exo-trig cyclization processes are the fastest and have thus been applied with success for the construction of 5membered ring carbocycles (Scheme 76). Cyclization of alkyl

Scheme 77. TTMSS-Mediated 5-exo-dig Radical Cyclization and Formation of Carbocycles

Scheme 76. TTMSS-Mediated 5-exo-trig Cyclization and Formation of Carbocycles

The 6-exo radical cyclizations onto arenes have been reported by Ohmori, Suzuki, et al. during their total synthesis of cavicularin, a natural polycyclophane (Scheme 78).196 Radical Scheme 78. TTMSS-Mediated Radical Cyclization onto Aromatic Systems

radical from iodide 263 was thus shown to provide complex polycyclic compound 264, albeit in moderate yield using the TTMSS-AIBN couple.189 Environmentally benign solvent such as benzotrifluoride may advantageously replace benzene in 5-exotrig radical cyclization as illustrated with the conversion of 265a− 265b into the corresponding spiro derivatives 266a−266b, which occurred in slightly higher yields than in benzene.190 In the course of their synthesis of Isodon diterpene Sculponeatin N,191 Zhai et al. reported the cyclization of vinyl radical produced from vinyl bromide 267 using TTMSS, in the presence of Et3B as an initiator, which led to the desired 5-exo-trig product 268a, along with the 6-endo and thermodynamically more stable 268b in a 2.5:1 ratio at 25 °C.192 The 5-exo-trig cyclization of the ketyl radical of aldehyde 269 led to cyclopentane 270, a marine

transannulation of iodide 273 thus formed the complex polyarene 274, which was obtained in good yield along with minor amount of deiodinated product, when using TTMSS as a hydrogen donor. In a similar way, ortho-bromo arene 275 was converted into polyaromatic compound 276 using a TTMSSmediated 6-exo radical cyclization, followed by a final aromatization under acidic conditions.197 TTMSS-mediated 6exo cyclization of acyl radical was used as a key step by Bennasar et al.198 to get pentacyclic phenol 278 from selenoester 277 in their total synthesis of calothrixin B (Scheme 78).199 Formation of 278 proceeds through the formation of an acyl radical, generated by abstraction of the PhSe group in 277 by the (TMS)3Si• radical, followed by cyclization onto the heterocyclic moiety and final rearomatization-overoxidation sequence. The 6541


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same authors used this strategy to access analogues of the ergoline alkaloid family.200 Medium-sized rings are known to be difficult to assemble. TTMSS however allows intramolecular radical addition of Ccentered radical onto enones to take place, to build 7-membered ring systems. Li et al. have used the ability of TTMSS to transfer hydrogen atom with low rate to construct the 7-membered ring of daphenylline through treatment of iodide 279 with TTMSS and AIBN (Scheme 79).201 The 7-exo-trig radical cyclization

Scheme 80. TTMSS-Mediated Ueno-Stork Radical Cyclization

Scheme 79. TTMSS-Mediated 7-exo- and 7-endo-trig Alkyl Radical Cyclization

cyclization, then final reduction with TTMSS, led to the desired siloxy-substituted tetrahydrofuran 289 in reasonable yield (Scheme 81).207 The 5-exo-trig cyclization of the electrophilic

proceeds with complete diastereocontrol as a result of the important stereochemical bias of the system to give compound 280 in nearly quantitative yield. A rare example of 7-endo-trig cyclization was recently reported by Inoue and co-workers during their studies on the total synthesis of Euphorbiaceae crotophorbolone.202 The ring junction between stereocenters at C9 and C10 was installed stereospecifically through the 7-endo cyclization onto the cyclopentenone 281, while the remaining C4 stereocenter was controlled during the hydrogen atom transfer from TTMSS, leading to 282 as a single diastereomer.

Scheme 81. TTMSS-Mediated Alkoxy Radical Cyclization and Formation of Tetrahydrofurans

6.2. Formation of Heterocycles

6.2.1. Formation of Oxygen-Containing Heterocycles. Ueno-Stork radical cyclization constitutes a straightforward method for the access to tetrahydrofuran and butyrolactone skeletons. This strategy was elegantly used by Peng and coworkers to build the skeleton of antimalarial 2,7′-cyclolignans (Scheme 80).203,204 Treatment of acetal 283 with TTMSS thus led to 5-membered ring after 5-exo-trig radical cyclization, followed by reduction of the primary radical with the silane, albeit with poor stereocontrol. The syntheses of CF3- and SF5-containing dihydrobenzofurans (285a and 285b) were achieved using an intramolecular reductive radical cyclization from readily available acyclic precursors such as 284a and 284b, respectively.205 The heterocycles were obtained in moderate to excellent yields and further oxidation with DDQ afforded the corresponding benzofurans. The key fragment of the marine macrolide iriomoteolide-2a was prepared via a highly stereoselective radical cyclization of a vinyl ether intermediate; indeed, treatment of the iodide 286 with TTMSS in the presence of triethylborane gave rise to the cyclized product 287 in 99% yield as the sole diastereomer.206 Sammis et al. recently devised an elegant cascade process to elaborate tetrahydrofuran skeleton based on a TTMSS-mediated generation of an alkoxy radical from 288. Subsequent 5-exo-trig

alkoxy radical is favored relative to competitive 1,5-hydrogen abstraction or β-fragmentation processes. Interestingly, the strategy was also successfully extended to the formation of various tetrahydrofurans with reasonable to good diastereocontrol as well as to tetrahydropyrans. An enantioselective access to tetrahydrofurans such as 291 was also developed relying on a 5-exo-trig cyclization of the carboncentered radical derived from the iodoalkene 290, mediated by a zinc-bisoxazoline complex as a chiral inducer and TTMSS as the hydrogen atom donor (Scheme 82).208 Stereodifferentiation is thought to occur through the binding of one of the sulfone oxygen of 290 with the zinc-bisoxazoline complex. 6-Exo-trig cyclization was carried out similarly to build the analogous pyran skeleton. In the course of their total synthesis of 19-hydroxysarmentogenin, Inoue and co-workers elaborated the fused tricyclic system of the natural cardenolide relying on a 6-exo-trig cyclization of a 6542


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Scheme 82. Enantioselective Formation of Tetrahydrofurans Through TTMSS-Mediated 5-exo-trig Radical Cyclization

Scheme 84. TTMSS-Mediated Formation of the Lactone Ring through Intramolecular Radical Addition of a Selenocarbonate onto an Enol Ether

these reactions to initiate reactions and as hydrogen atom donor. Recent progress in this field may be summarized as depicted in Figure 2, with the radical formation of heterocycles, following

carbon radical generated from bromide ether 292 using TTMSS (Scheme 83).209 Addition, then reduction of the enoyl radical Scheme 83. TTMSS-Mediated Formation of Pyran Rings

Figure 2. Radical reactions in the formation of nitrogenated heterocycles.

two main routes, one involving the addition of C-centered alkyl radicals onto an unsaturated bond (olefin double bond or arene, route A) and a second one where an aryl radical is added onto the same type of unsaturated systems (route B). Cyclization reactions of α-halo amides provide a straightforward entry toward bicyclic lactams. Heinrich et al.215 studied the influence, on the s-cis/s-trans conformation, of the n−π* interaction between the CO oxygen and various substituents on the nitrogen center and the consequence on the course of radical cyclizations (Scheme 85). Hydrogen-bonding between the N(H)Boc substituent and the carbonyl in 299a was shown to favor the s-cis conformation and thus cyclization of the α-amido alkyl radical into 300a, relative to its reduction. Lower amount of cyclized product 300b was observed with the n-Bu analogue 299b, lacking such interactions. Radical intramolecular αalkylation of ketones such as 301 through the corresponding enamine has also been developed by Diaba, Bonjoch, and coworkers using a radical polar crossover process.216,217 The onepot reaction mediated by TTMSS and AIBN occurs under microwave activation and proceeds through the alkyl radical cyclization of the α-chloroacetamide onto the in situ generated enamine in I, leading to the corresponding α-amino alkyl radical, which is oxidized into the iminium salt II. The latter may also be formed through the chlorine atom transfer to the α-aminoalkyl radical and elimination of HCl. Hydrolysis of the final enamine, followed by reduction of the C−Cl bond by TTMSS then leads to a series of cyclization products, including 302, the azatricyclic core of natural product FR901483. TTMSS-mediated 6-exo-trig cyclization of alkyl radicals produced from bromides 303 was also developed to access diastereomeric piperidines 304a and 304b with moderate to high level of diastereocontrol, depending essentially on the nature of

with TTMSS, led to 293, an advanced intermediate in the total synthesis, in excellent yield. The pyran-3-one 295 was assembled by Hirama et al., starting from selenoester 294 through a TTMSS-mediated 6-exo acyl radical addition onto an enol ether, albeit in modest yield.210 Product 295 was formed along with complex polycyclic compound 296, resulting from a more favored 5-exo-trig cyclization of the acyl radical at C21. Formation of the lactone was followed by a second 5-exo-trig radical cyclization between C22 and C15 centers. Zakarian et al. showed that TTMSS was best able to perform the 6-exo-trig acyl radical cyclization of the selenocarbonate moiety onto the enol ether in 297, generating the lactone ring of 298 in reasonable yield, along with 14% of the main side product (not shown) resulting from the decarboxylative fragmentation of the acyl radical (Scheme 84).211,212 In contrast, Bu3SnH mainly afforded the corresponding formate ester (84%). The lactone ring was also formed through intramolecular addition of alkyl radicals generated from α-bromo esters onto oxime ethers, using TTMSS and Et3B.213 6.2.2. Formation of Nitrogen-Containing Heterocycles. Formation of nitrogen-containing heterocycles, including natural alkaloids, through radical processes and cascades, has been thoroughly studied over the years.214 TTMSS is often used in 6543


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the origin of the diastereoselectivity, which expectedly improves as R1 size increases. In contrast, the nature of the R2 group on the ester has little influence on the stereocontrol. Related 6-exo alkyl radical addition, onto an arene, has been reported by Ragains et al.220 during their synthesis of γ-lycorane (Scheme 87).221 TTMSS-mediated addition of the alkyl radical onto the arene fragment of 305 led to tetracyclic 307 along with reduced product 306. TTMSS was shown to be superior to the Bu3SnH-promoted radical cyclization that afforded exclusively 306. TTMSS was shown by Chatgilialoglu and co-workers to mediate the 6-exo-cyclization of an aldehyde function onto the adenine moiety in the compound 308 to afford the cyclonucleoside 309 in 75% yield (Scheme 88).222,223 The reaction proceeds

Scheme 85. TTMSS-Mediated 5-exo and 6-exo-trig Radical Cyclizations of α-Chloroacetamides

Scheme 88. TTMSS-Mediated Cyclonucleoside Formation Through 6-exo-trig Radical Cyclization

the R1 substituent in the α-position to nitrogen (Scheme 86).218,219 A1,3 strain induced by the R1 group is supposed to be at Scheme 86. Diastereocontrolled Access to Piperidines Through TTMSS-Mediated 6-exo-trig Radical Cyclization

through the addition of (TMS)3Si• radical onto the aldehyde to afford the C-centered radical I. The latter then cyclizes stereoselectively onto the nucleoside to generate the dearomatized intermediate II. Oxygen is thought to favor the rearomatization of the system into the cyclonucleoside 309.224 A Scheme 87. TTMSS-Mediated 6-exo-trig Alkyl Radical Cyclization onto Arenes

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acyclic precursors such as 316a and 316b, respectively.205 In the case of CF3-derivatives TTMSS (2.5 equiv) and AIBN (0.25 equiv) had to be used, whereas in the case of SF5-derivatives increased amounts of both TTMSS (3 equiv) and AIBN (0.3 equiv) were necessary to provide higher conversions. The 2-bromopyridine reagent 318 was transformed into the corresponding imine 319 via Staudinger reduction using polymer-bound Ph3P followed by an aza-Wittig reaction with the chosen aldehyde. Imine 319 reacted smoothly with TTMSS and AIBN in toluene at 100 °C providing the cyclized product 320 (Scheme 90).233 Three examples of 1,7-tetrahydronaph-

related cyclization was developed starting from bromo derivative 310. TTMSS was shown to promote the bromine abstraction, which was followed by a 1,6-hydrogen transfer, to provide a radical intermediate similar to I. 6-Exo cyclization onto the nucleoside ring then led to cyclonucleoside 311 in high yield and good stereocontrol (Scheme 88).225,226 These cyclizations are worth noting as they are related to tandem-type lesions occurring in DNA modifications. A somewhat linked TTMSS-mediated 6exo-trig cyclization of a primary alkyl radical onto the CC bond of a uracil moiety has been reported to generate analogous cyclonucleosides under a variety of initiation methods, including black light.227 Aryl radicals are very reactive and efficiently add onto olefins as illustrated with the 5-exo-trig cyclization of the radical generated from precursor 312, which led to indole 313 in high yield in Tietze’s synthesis of duocarmycin analogues (Scheme 89).228

Scheme 90. Synthesis of Tetrahydronaphthyridines

Scheme 89. TTMSS-Mediated 5-exo- and 6-exo-trig Cyclization of Aryl Radicals onto Olefins

thyridines 320 together with the corresponding yields are reported. Construction of the regioisomeric 1,6- and 2,7tetrahydronaphthyridine derivatives was obtained similarly by choosing the two suitable components for the reaction, and two representative examples 321 and 322 are shown, respectively. Such products are formed in a predictable manner via a formal Pictet-Spengler reaction of electron-poor pyridines that would not participate in the corresponding polar reactions. Paixão and co-workers developed an interesting access to various indoles (e.g., 324, Scheme 91), based on a visible-light mediated 5-exo-dig cyclization of aryl radical generated from propargyl tosylamines such as 323 using TTMSS as a mediator.234 The reaction is believed to proceed through abstraction of the iodide atom by the (TMS)3Si• radical, itself generated from a colored electron donor−acceptor (EDA) complex, formed between the sulfonamide and TTMSS, and irradiation with a 15 W CFL bulb. It is suggested that the reaction

This strategy is commonly used for the access to duocarmycin antitumor agents.229,230 Consecutive 5-exo-trig/5-exo-trig radical cyclizations were studied by Sapi et al. using TTMSS as final hydrogen atom donor.231 It is worth noting that the nature of the N-protecting group in 314 is important here as to favor the s-cis conformation of the amide bond and thus the second cyclization. The 6-exo-trig cyclization of aryl radical generated from sulfonamide 315 has also been described by Piva et al. and led to cyclic sulfonamide in generally good yield.232 The syntheses of CF3- and SF5-containing indolines 317a and methyl-substituted indolines 317b were achieved using an intramolecular reductive radical cyclization from readily available 6545


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Scheme 91. Visible-Light TTMSS-Mediated Synthesis of Indoles (Upper Part) And Indolines (Lower Part)

Scheme 92. TTMSS-Mediated Cyclization of Aryl Radicals onto Arenes

is not a radical chain process, indole 324 being formed after 5exo-dig cyclization of aryl radical, 1,3-hydrogen shift, and final reduction of the allylic radical center by ethanol. The reaction was also extended to 5-exo-trig cyclization of aryl radical to form the corresponding oxindoles. The same group developed an intramolecular radical cyclization approach to access highly substituted indolines (Scheme 91) and 2,3-dihydrobenzofurans.235 A variety of substrates type 325 in the presence of 2 equiv of TTMSS and visible-light afforded 326 in good yields (3 examples are shown) in the absence of transition metal and additional photocatalyst. Intramolecular aryl radical addition onto arenes constitutes a general, straightforward and efficient strategy to access biarylic systems. Such C−C bond forming process was recently reported by SanMartin, Dominguez, et al. for access to the pyrazolophenanthridine skeleton as in 328 in modest to excellent yields, regardless of the electronic nature of the substituents (Scheme 92).236 The bromine atom in precursors 327 can be located onto one aromatic ring or the other without consequences. This method was shown to provide an efficient alternative to transition metal mediated C−C bond formation. Closely related cyclizations also allow the construction of 5-membered ring systems,237,238 as in the synthesis of rosettacin from aryl chloride 329. In this case, a minor amount of reduced product (26%) was also formed (when using 2 equiv of TTMSS). In both cases, (TMS)3Si• radical generated from TTMSS abstracts the halogen

(Br or Cl), which is followed by the radical cyclization and then rearomatization. The use of 2 equiv of TTMSS, with precursors such as 329, led to the cyclized product (not shown) in which the nitrogenated ring was further reduced.78 The same approach was developed for the access to water-soluble topoisomerase inhibitor 14-azacamptothecin from precursor 330, albeit in modest yield.239 Radical arylation of pyridinium rings as in 331, through a 6-exo/6-endo type cyclization, has also been reported, leading to salt 332 in moderate yields.240 It was shown that better yields are consistently obtained when electron-donating groups (OMe) are present on the aromatic moieties.241 Similar studies was reported by Khlebnikov et al. starting from (2bromophenyl)pyrrolyl-1,2,4-triazoliums, affording the corresponding cyclized products in moderate yields.242 An interesting intramolecular radical addition of an aryl radical generated from aryl iodides 333a−333b onto an aryl azide was shown to proceed in the presence of TTMSS, affording spirodienones 334a−334b after hydrolysis of the resulting iminium salts.243 This approach 6546


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affords 5- and 6-membered ring spirodienones with satisfying overall yields. Vinyl radical generated through addition of a silyl radical onto an alkynone (335, Scheme 93) was reported to add onto arene,

Scheme 95. TTMSS-Mediated Radical Cyclization of Trinaphtylboranes

Scheme 93. Addition of (TMS)3Si• Radical onto Alkynone and Cyclization of a Vinyl Radical onto an Arene

affording the corresponding dienone in good yield.244 Various silanes, including TTMSS, were used with high efficiency. The reaction proceeds through the Fe(II)-catalyzed decomposition of t-BuOOH and formation of a t-BuO• radical, which then abstracts a hydrogen from the silane. Addition of the silyl radical onto the ynone is followed by a 5-exo-trig cyclization at the ipsoposition, leading to a cyclohexadienyl radical, finally trapped by the Fe(III)−OH species, affording the final product with the regeneration of the Fe(II) catalyst. Heterocycles such as 336 containing both nitrogen and oxygen were recently prepared by Alexanian et al. using an intramolecular addition of amidoxyl radicals onto alkenes using dilauroyl peroxide (DLP) as an initiator and TTMSS as an hydrogen atom donor (Scheme 94).245 Renaud et al. have

7. TTMSS AS A MEDIATOR OF REARRANGEMENTS 7.1. Radical Rearrangements

TTMSS has often been used in radical rearrangement processes as the relatively strong Si−H bond allows reorganization, bond breaking, and bond formation prior to reduction. Arylsulfonyl group transfers have gained a broad interest as they allow the formation of biaryl systems in a straightforward and reliable manner.249 Sapi and co-workers have thus shown that treatment with TTMSS and ACCN of amide 341, bearing a sulfonamide group, triggered a 5-exo-trig radical cyclization, which was followed by an aryl group transfer from the sulfonamide, and the formation of a C-aryl bond (Scheme 96).250 The cascade event was observed providing that heating in decane at 174 °C was performed, leading to the desired product 342 and analogues with satisfying yields. Recent studies by Lambert et al. used TTMSS and iodine as an initiator to trigger the transfer of an aryl group from sulfonates and sulfonamides of type 343 to afford a broad variety of polysubstituted biaryl compounds 344.251 The reaction proceeds through an ipso-addition of the aryl radical onto the arylsulfonyl moiety leading to a spirocyclohexadienyl intermediate I, which then evolves through a C−S bond breaking, and the loss of SO2 into an alkoxy or an aminyl radical II, eventually trapped by TTMSS. A catalytic version under photoredox conditions was also devised using a tertiary amine as the terminal reductant, but the scope was slightly reduced as compared to the TTMSS method. Biaryls may finally be prepared from carbamates such as 345, relying on an unusual 1,6-ipso substitution process, shown to be more favorable than the alternative 1,7-addition reaction.252 Treatment of pyridine carbamate 345 in the presence of TTMSS and ACCN thus led to the corresponding biaryl 346 with modest to good yields, after 1,6-ipso substitution process, decarboxylation of the corresponding carbamoyloxyl radical, and final reduction of the aminyl radical with TTMSS. 1,5-Hydrogen transfer may be followed by oxidation of the radical generated upon translocation, as illustrated with the functionalization α-carbon to nitrogen in hydroxyproline 347 (Scheme 97).253 The 1,5-HAT from the primary alkyl radical, itself generated through (TMS)3Si• radical abstraction of the bromine atom, generates a new stabilized radical in the αposition to nitrogen. Oxidation of the latter with Cu(II) then produces an iminium which is trapped by an acetate ion from Cu(OAc)2 to afford 348 in good yield.

Scheme 94. Radical Cyclization of Unsaturated Hydroxamic Acids and Synthesis of Indolines from Aryl Azides

described an unusual access to the indole ring based on a 5-exotrig cyclization of a C-centered radical onto an aryl azide (Scheme 94).246 The alkyl radical is generated through abstraction of iodine atom from 337 by the (TMS)3Si• radical. It then cyclizes onto the azido substituent to furnish the indoline 338 in moderate yield, after loss of N2 and trapping of the final aminyl radical with TTMSS. 6.2.3. Formation of Boron-Containing Heterocycles. Boron-containing heterocycles are not so common and may be prepared through radical-based methods. Yamaguchi and coworkers exemplified several of these cyclizations as illustrated in Scheme 95. Three-fold intramolecular radical cyclization of trinaphthylborane 339a led to the planar system 340a having interesting photophysical properties.247 Biaryl coupling in 339b also led to planar boron heterocycle 340b in better yield through TTMSS-mediated radical cyclization.248 6547


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reaction, is well-adapted for this purpose as illustrated in examples below (Scheme 98).255,256 Pioneering studies were carried out on cyclopentanone 349, which ring-expansion led to cyclohexanone 350 through intermediates I and II. Hasegawa et al. described the ring expansion of compound 351 in the presence of TTMSS in benzotrifluoride as a solvent under reflux, which led to 352 in modest yield (Scheme 98).190 Interestingly, when the reaction was carried out with TTMSS in benzene, no

Scheme 96. TTMSS-Mediated Aryl Group Transfer for Sulfonates, Sulfonamides, and Carbamates

Scheme 98. TTMSS-Mediated Beckwith-Dowd Radical Ring Expansion

Scheme 97. TTMSS-Mediated 1,5-HAT Followed by Oxidation of Alkyl Radical

Beckwith-Dowd ring expansion is a relatively slow process (k = 1.4 × 105 s−1 at 100 °C),254,255 so that low concentration of hydrogen atom donor (slow addition) is generally required. TTMSS, which was used to determine the mechanism of the 6548


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stabilized radical II, eventually trapped by TTMSS, furnishing 362 in good yield. The reaction was also applied to a L-sorbose derivative. Substituted thiocarbonylbenzotriazoles such as 363 are converted into amino- and thiobenzothiazoles 364 in generally high yields through the decomposition of the benzotriazole ring.262 The reaction is believed to proceed through the addition of the (TMS)3Si• radical onto the thiocarbonyl moiety, with consecutive extrusion of nitrogen and attack of the corresponding aryl radical onto the sulfur center.

reaction was observed, while Bu3SnH in benzene led to 352 in 75% yield, emphasizing on the unique role of benzotrifluoride as a solvent in radical transformations. Beckwith-Dowd ring expansion followed by cyclization gives rise to polycyclic systems as well as medium size rings, which are difficult to access otherwise. Hierold and Lipton have recently provided an elegant illustration of this strategy. Slow addition of TTMSS onto 353 led to the spirolactone 354 as the only product.257 Using similar conditions, better hydrogen atom donor Bu3SnH provided 354, along with the Beckwith-Dowd ring expansion product. Lactones spirofused to larger cycloalkanones such as 356 were also accessible from ketoester 355, using this strategy. Supported by DFT calculations, Beckwith-Dowd radical ring expansion was invoked to rationalize the puzzling cyclization of closely related bromopyridines 357a−357b, which led to the quinazolinium bromide 358a and quinolone 358b, respectively, after ipsoaddition of the aryl radical onto the quinoline ring and rearrangement through intermediates III and IV.258 The cyclobutylmethyl radical is known to fragment easily (k = 5 × 103 s−1), although at a slower rate than the corresponding cyclopropyl analogue (k = 6.7 × 107 s−1).259 An interesting example of such rearrangement is provided with the quantitative TTMSS-ring expansion of 359 into the seven-membered ring 360. TTMSS was shown to be more selective than tin and germanium analogues due to its bulkiness (Scheme 99).260

7.2. Cascade Radical Processes

Radical annulation strategy has been developed to afford an efficient access to polycyclic systems from simple and readily available precursors. Consecutive C−C bond formation is allowed by the careful choice of elementary steps of known kinetic data and the use of TTMSS as a radical initiator. An example of such annulation process was developed by Curran and Du for the preparation of quinoline 366 from Narylthiocarbamates such as 365 (Scheme 101).263 Reaction of Scheme 101. TTMSS-Mediated Radical-Based Annulation Strategy

Scheme 99. TTMSS-Mediated Cyclobutane Ring Expansion

An unusual group transfer process mediated by TTMSS was reported by Chang et al. to convert D- and L-ketohexoses into rare 3-deoxy-L-ketohexoses.261 The rearrangement is initiated through cyclization of a C-centered radical onto the ketone moiety of fructose derivative 361 to generate intermediate I (Scheme 100). β-Fragmentation then occurs to provide the more Scheme 100. TTMSS-Mediated Group Transfer and Rearrangement

the (TMS)3Si• radical under photochemical conditions at the sulfur center of thiocarbamate 365 generates a C-centered radical I, which then adds in a 5-exo-dig fashion onto the alkyne moiety, forming a reactive vinyl radical II. The latter then cyclizes in a 6exo mode onto the arene to form the final tricyclic system. Oxidative rearomatization and ionic loss of a silylthiol finally provides quinoline 366 in moderate yield. Oxygen-containing heterocycles are also accessible using such tandem processes as illustrated by the conversion of bromide 367 into the polycyclic system 368, related to the skeleton of guttiferone, a 6549


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the aryl iodide, followed by the 5-exo/5-exo cyclization, led to the corresponding amine, which was methylated in situ to afford 374 in a good overall yield. A Birch reductive removal of the benzyl protecting group led finally to horsfiline. Parker and co-workers have recently reported an elegant total synthesis of (±)-bisabosqual A, isolated from Stachybotrys metabolites as a result of a screening for inhibition of microsomal squalene synthase.268 The elaboration of the tetracyclic skeleton of bisabosqual A from iodide 375, encompasses a 5-exo/6-exo radical cyclization cascade, through radical species I and II, which setup two rings and control three of the five stereogenic centers of natural product intermediate 376 (Scheme 103). Bisabosqual A was finally reached after 14 steps starting from commercially available starting materials.

polyprenylated acylphloroglucinol natural product (Scheme 101).264 Consecutive 5-exo/5-exo cyclization mediated by the (TMS)3Si• radical proceeds through intermediates III and IV, allowing the elaboration of the complex structure of 368 in good yield. Renaud et al. recently described a 5-exo/5-exo cascade to elaborate the skeleton of Aspidosperma alkaloids, relying on the Ueno-Stork strategy (Scheme 102).265 Abstraction of the iodine Scheme 102. TTMSS-Mediated 5-exo/5-exo Radical Cascades

Scheme 103. TTMSS-Mediated 5-exo/6-exo Radical Cascades

(TMS)3Si• radical readily adds onto double bonds, a feature which was put to profit by Pattenden and co-workers to trigger radical cyclization/fragmentation cascades, giving rise to bicyclic systems such as 378 starting from allene 377 (Scheme 104).269 The transformation proceeds through the addition of the silyl radical onto the double bond of 377 to provide I and is followed Scheme 104. TTMSS-Mediated Cyclization/Fragmentation Radical Cascades atom of 369 by the (TMS)3Si• radical, followed by the double cyclization, led to the indole N-centered radical species, which was finally reduced by TTMSS into 370, thus completing the radical chain. Ryu and Murphy et al. built the indole ring of spirocyclic indole-γ-lactams using similarly an azido group to trap the final C-centered radical.266 Product 372a was thus obtained after a 5-exo cyclization of the aryl radical, generated from iodide 371a onto the enamide to afford I. The latter then added onto carbon monoxide to provide the acyl radical II. A second 5-exo radical cyclization on the azide led to III, the reduction of which provided 372a. The cascade was also extended to the synthesis of oxygen and sulfur heterocyclic analogues. Interestingly, when the reaction was performed using the unprotected compound 371b, a 6-endo radical process prevailed, which was followed by the βelimination of the azido substituent and a final addition of the THF radical (formed through abstraction of a hydrogen atom from THF by the •N3 radical) to form 372b. A concise synthesis of alkaloid horsfiline was developed based on a similar cascade but using homologous precursor 373.267 TTMSS reduction of 6550


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trig process to furnish a carbon radical trapped stereoselectively by the bulky TTMSS, leading to a cyclic siloxane (not shown) converted into 382 through addition of MeLi in a remarkable 92% overall yield. A related example of the high reactivity of vinyl radicals and their use in cascade process was reported recently by Kamimura and co-workers.273 Addition of the (TMS)3Si• radical onto electron-poor olefins is a fast process, which may be followed by further functionalization of the resulting radical, as illustrated by the conversion of enyne 383 into dihydrosilole 384. The latter is formed through the 5-exo-dig cyclization of radical intermediate I, generating vinyl radical II. Interestingly, the latter is not reduced by TTMSS but reacts instead at the central silicon atom of the (TMS)3Si group (SHi), affording 384 and a Me3Si• radical. When the reaction was carried out without solvent (Ar = Ph), the authors observed not only that yield was higher (72% vs 58%) but also that a byproduct was formed in trace amount (5%), resulting from the addition of the Me3Si• radical onto 383, followed by the same 5-exo-dig radical cyclization and final reduction of the vinyl radical. Varying the nature of the aryl group led to various dihydrosiloles with satisfying yields and high diastereocontrol in the favor of the trans-isomer (7:3 to 9:1). With the exception of the case when the Ar ring is 4-CF3C6H4, no epimerization at the benzylic center was observed under the reaction conditions. Such SHi reaction at silicon has some precedents in the literature and was observed by Chatgilialoglu and Giese during their seminal studies on TTMSS reactivity274 and by Oshima et al. on the closely related cyclization of the radical generated from vinyl bromide 385, mediated by TTMSS, which formed bicyclic product in good yield.275 This approach has been used as an entry to Si-containing heterocycles. A variety of substituted N-(2-(ethynyl)aryl)acrylamides 386a in the presence of 2 equiv of TTMSS and tert-butyl peroxybenzoate (TBPB) as radical initiator at 120 °C afforded 4H-silolo-[3,4c]quinolin-4-ones 386b in moderate to good yields.276 (TMS)3Si• radical efficiently abstracts halogens (Br or I) from aryl halides to generate very reactive aryl radicals, which are prone to abstract hydrogen atoms, leading to more stable Ccentered radicals. The 1,5-hydrogen atom transfer (1,5-HAT) from Csp3-H to aryl radical has for instance been used recently by Tokuyama and co-workers in their total synthesis of (−)-histrionicotoxin.277 Radical abstraction of the bromine atom of 387 by the (TMS)3Si• radical thus provides aryl radical I (Scheme 106). The 1,5-HAT then leads to the electron-rich α-amino radical II, which cyclizes in a 6-exo-trig fashion to afford, after reduction, spiroamide 388 in good yield and high diastereocontrol. Interestingly, X-ray diffraction studies on a derivative of 388 indicates that the configuration of one of the acetal methyl substituent has been inverted during the process. This may be rationalized invoking conformations A and B, resulting from the 6-exo-trig radical cyclization. In the major isomer, the chair conformation of the acetal A is believed to flip to allow for a 1,5HAT as shown in Scheme 106, the resulting α-alkoxy radical being then reduced by TTMSS in a fast step. In contrast, conformation B of the minor isomer does not allow such an intramolecular hydrogen transfer, B being then reduced by TTMSS in a slow process due to steric congestion. This proposed mechanism thus explains the relative configurations of 388 and that of the minor diastereomer but also the higher diastereocontrol observed with TTMSS as compared to Bu3SnH and Ph3SnH. Related 1,5-HAT was recently disclosed by Beaudry et al. in aminals such as 389.278 TTMSS was shown to allow the formation of the aryl radical. The latter then abstracts the hydrogen of the aminal C−H bond forming an electron-rich

by a 5-exo radical cyclization leading to highly strained II which then fragments, affording 378 after the reduction of the final Ccentered radical by TTMSS. The reaction was also extended successfully to 6,6-bicyclic analogues, but failed to provide 6,7bicyclic homologues resulting from a 7-exo radical cyclization process. Similar 6-exo radical cyclization/fragmentation has been devised by Luo et al. to construct the decalin skeleton of (−)-hibiscone C (Scheme 104).270 The formation of synthon 380 occurs with high yield and diastereocontrol through the 6exo-trig cyclization of ketyl radical onto the electron-poor olefin of 379, followed by the fragmentation of the 4-membered ring of the pinene-type fragment, the final radical being trapped by TTMSS. 5-Exo-dig cyclization have been used extensively in radical tandem reactions as they generate a reactive vinyl radical, which allows further transformation. Malacria and co-workers reported a striking example of such cascade process starting from a 5-exodig radical cyclization (Scheme 105).271,272 TTMSS-mediated 5exo cyclization of an α-silyl bromide 381 was thus followed by a 1,5-hydrogen atom transfer to generate a new C-centered radical at the acetal carbon center. This then cyclized through a 5-exoScheme 105. TTMSS-Mediated 5-exo-dig Radical Cyclization/SHi Cascades

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Scheme 106. TTMSS-Mediated 1,5-Hydrogen Atom Transfer/Radical Addition Cascades

Scheme 107. TTMSS-Mediated Radical Carbonylation Process

Scheme 108. TTMSS as a Reducing Agent in Pd- and NbCatalyzed Reactions

radical, which can add onto electron-poor olefins, in an inter- or intramolecular fashion. It is noteworthy that yields are improved using BnSH as a hydrogen donor. Using this strategy, 389 was thus converted into 390 and its cyclized form 391 in high yield (Scheme 106). 7.3. Miscellaneous Reactions

Following Ryu’s pioneering carbonylation method,279 Odell, Eriksson, et al. described a low-pressure radical 11C-aminocarbonylation of alkyl halides. This method relying on a xenonbased [11C]CO delivery unit provides an efficient access to 11Clabeled amides with useful conversion (relative to the amount of [11C]CO).280 (TMS)3Si• radical is used to generate the Ccentered radical from the alkyl halide 392 (Scheme 107). This radical species is then carbonylated, leading to an acyl radical which abstracts iodine from 392. The final acyl iodide affords amide 394 through addition of amines 393. A similar protocol was reported previously that provides 11C-labeled esters using alcohols.281 Silanes including TTMSS are often used as reducing agents in transition-metal-catalyzed processes. Chatani et al. have used this property during the development of a synthetic access to dibenzofused 6-membered ring phosphacycles such as 396 from substituted triarylphosphines 395 (Scheme 108).282 The method affords phosphazoles 396 in high yield and is compatible with a wide range of functional groups (esters, amides, and carbamates). The reaction proceeds through an oxidative addition of a Pd(0) species I onto the C−Br bond of 395, leading to intermediate II. The C−P bond forming reductive elimination generates III and a Pd(0) species. The C−P bond of III may be cleaved through

oxidative addition to Pd(0), leading to 396 along with Ph−Pd− Br, the reductive elimination of which is thermodynamically unfavored. The latter is thus reduced by TTMSS to afford PhH and (TMS)3SiBr, regenerating catalyst I. TTMSS improves catalyst turnover and was found to be more efficient than other less hindered silanes [Et3SiH and (EtO)3SiH], which are believed to reduce palladacycle II too early. TTMSS was also used to generate low-valent niobium species such as IV through in situ reaction with NbCl5 and an alkyne (e.g., 397, Scheme 108).283 Oxidative cyclometalation of two molecules of alkynes likely provides a niobium complex, which eventually reacts with an alkene (e.g., 398) to afford fused dienes such as 399.284 6552


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8. APPLICATIONS OF (TMS)3SiH IN POLYMERIZATION Photoinitiated (PI) polymerization has been the subject of continued research efforts due to the numerous applications of this technique (coatings, inks, adhesives, optoelectronics, laser imaging, stereolithography, and nanotechnology, etc.).285 The recent discoveries of photoredox catalysis developed by organic chemists have been implemented by polymer chemists to provide high reactivity with low catalyst loading, permitting access to high performance PI systems.286,287 During the past decade, the use of TTMSS as an active part of PI systems for polymerization processes has been above the expectation. The (TMS)3Si• radical associates with properties of great importance for applications in polymerization initiating systems, such as the high reactivity of the silyl radicals for the addition to double bonds and the relatively low oxidation potential for the formation of silylium cations.288,289 Indeed, in free radical promoted cationic polymerization (FRPCP), the initiating cations are generated from oxidation of free radicals.290 Furthermore, the abilities of (TMS)3SiH to consume adventitious oxygen and trap peroxyl radicals by H-donation (see section 4.4) are also important characteristics to overcome the classical and wellknown oxygen inhibition of free radical polymerization (FRP) processes. In this section, some examples of recently developed photoinitiated systems based on the peculiar reactivity of (TMS)3SiH and its derived radical are presented for both FRP and FRPCP processes in the presence of air.

radicals must be very high and ideally close to 1 like in (TMS)3SiH. Different photoinitiators have been proposed in combination with (TMS)3SiH to extend the spectral sensitivity of these initiating systems (i.e., benzophenone, 2-isopropyl thioxanthone, camphorquinone, Eosin-Y, and thiopyrylium salts). Indeed, these systems effectively cover the wavelength range 300−600 nm,294 and proposed red light systems based on violanthrone photosensitizers may afford an extended spectral sensitivity up to 700 nm.295 Interestingly, the polymerization profiles for the acrylate matrix were found to be better than those obtained in the presence of a reference amine co-initiator, with an increase of both polymerization rates and final conversions. The effectiveness of (TMS)3SiH for improving the initiation process under air was excellent, and the usual oxygen inhibition of FRP was diminished. The drastic decrease of both polymerization rate and final conversion found generally for the FRP process under air is due to the reaction of initiating or propagating radicals with oxygen to give peroxyl radicals. (TMS)3SiH was found to overcome this oxygen detrimental effect in many FRP processes, the reason being its reaction with oxygen described in section 4.4 and depicted in Scheme 65. Scheme 109b illustrates how the silyl radical 400 transformed with oxygen and generates another more reactive silyl radical 401 that reacts with the precursor (TMS)3SiH to regenerate 400 (cf. Scheme 65). Moreover, the oxygen inhibition for the FRP process is usually associated with stable peroxyl radicals or the photodecomposition of the hydroperoxides formed under air. In the presence of (TMS)3SiH, peroxyl radicals and other oxy-type species are readily trapped to afford a new initiating (TMS)3Si• radical, which is highly worthwhile to overcome the oxygen inhibition. All these processes explain quite well the excellent initiating ability found for PI systems based on (TMS)3SiH. Scheme 110

8.1. Photoinduced Free Radical Polymerization (FRP)

As we mentioned in section 1.2, a large number of rate constants are available for the reaction of a variety of radicals with TTMSS. For example, the photogenerated tert-butoxyl radical (t-BuO•) as well as the benzophenone triplet state (3BP) abstract hydrogen with rate constants close to 1.1 × 108 M−1 s−1 at room temperature. The ketyl or silyl radical quantum yields are close to 1 for (TMS)3SiH.141 The addition of (TMS)3Si• radical to a double bond of monomer (M) is efficient and can be followed by the subsequent addition of monomer units corresponding to a propagation reaction (Scheme 109a). The rate constants for the

Scheme 110. Proposed Role of TTMSS in Reducing Oxygen Inhibition of Photopolymerization

Scheme 109. (a) (TMS)3Si• Radical As an Initiator for Free Radical Polymerization and (b) Consumption of Oxygen by (TMS)3Si• Radical

summarizes the excellent performance of TTMSS in free radical polymerization. Its antioxygen inhibition mechanism includes the consumption of oxygen and the interception of active oxygen radicals. TTMSS was photochemically attached to 1,4-butanediol divinyl ether, and the resulting diadduct treated with t-BuOK in absolute THF yields gave the desired difunctional bis(trimethylsilyl)silane. The radical reactivity of this compound in photoinitiated radical reactions with various homopolymerizable monomers has been studied in some detail. In particular, the silane−acrylate system was studied in greater detail.296

addition (kadd, M−1 s−1) of (TMS)3Si• to various alkenes decrease in the order: styrene 5.1 × 107, acrylonitrile 5.1 × 107, methyl acrylate 2.2 × 107, vinyl acetate 1.2 × 106, and vinyl ether 2.1 × 105.67,141 In the PI system, (TMS)3Si• radicals are generated by a hydrogen abstraction reaction from parent silane (called coinitiator). The hydrogen abstractor is either a radical generated from the photocleavage of PI or a PI excited state (e.g., triplet state of ketone).285,291−293 The quantum yields of the derived

8.2. Silane Radical Atom Abstraction (SRAA)

Considerable efforts were made in developing ways to prevent the use of metallic species in chemical transformations and polymerizations. In this context, silane radical atom abstraction (SRAA) was investigated as a metal-free alternative to atom 6553


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transfer radical coupling (ATRC).297 In this case, the activation of the bromo-terminated polymers formed by atom transfer radical polymerization (ATRP) was carried out by halogen abstraction with (TMS)3Si• radicals instead of copper (Scheme 111).298 The efficiency of this coupling method based on SRAA

Scheme 112. Possible Mechanism Involving TTMSS in the Free Radical Promoted Cationic Initiating System (PI = Photo-Initiator, *PI = Excited State of PI, R• = Radical Generated from Photo-Cleavage of PI)

Scheme 111. Silane Radical Atom Abstraction (SRAA) in the Coupling Procedure

constant of 3 × 108 M−1 s−1, regenerating silyl radicals.14 In addition, the antioxygen inhibition effect of TTMSS shown in Scheme 110 can drive into new active silyl radicals, which can be oxidized to silylium cations capable of initiating the cationic polymerization. A large range of photosensitizers were proposed, allowing an excellent covering of the 300−750 nm spectral range for the three-component systems: PI/(TMS)3SiH/Ph2I+ (see refs 287, 288, 291−293, 302, and 305−307). Remarkably, the high reactivity of the (TMS)3Si• chaininitiating systems allows polymerization in otherwise difficult conditions: (i) polymerization of low-reactivity monomers (e.g., epoxidized soybean oil (ESO) as a renewable epoxy monomer) and (ii) it does so under very soft irradiation conditions (sunlight, daylight, fluorescence bulbs, LED bulbs; light intensity < 10 mW/cm2).308 The high reactivity of silylium cations with epoxy is associated with the formation of a strong Si−O bond. The interaction energy between (TMS)3Si+ and cyclohexene oxide is found 70 kJ/mol higher than the interaction of cations derived from carbon-centered radicals (dimethoxybenzyl, ketyl, or aminoalkyl) with cyclohexene oxide.303

has been demonstrated for low molecular weight polystyrene (PS) precursors (Xc = ∼ 0.95, Mn0 = 1000−1500 g/mol).298 Therefore, SRAA efficiently promotes the coupling reaction of two halogen-terminated chains by massive generation of radicals followed by their recombination reaction (Scheme 111). The use of UV irradiation and photoinitiators was found to be less efficient, the radical coupling efficiency (Xc) being less than 0.57.299 A series of N-alkoxyamines were prepared by reaction of (TMS)3Si• radicals with alkyl halides in the presence of a nitroxide trap.300 SRAA procedure was used to abstract bromine termini from monobrominated polystyrene (PS−Br) in the presence of excess monomer and TEMPO, generating polymer radicals that underwent chain extension.301 Typically, 70−85% of the PS−Br precursors were activated by SRAA and were elongated by nitroxide-mediated polymerization (NMP). SRAA/NMP was then applied to the synthesis of polystyreneb-poly(n-butyl acrylate) and polystyrene-b-poly(p-methylstyrene).

8.4. Photoredox Catalysis (PC)

The use of soft irradiation conditions (sunlight, household green fluorescent bulb, or LED bulbs) for ring-opening photopolymerizations under air involved the development of highly sensitive systems, which need only a very low light intensity to drive the process, based on a recent approach proposed in organic chemistry for the formation of carbon-centered radicals with such irradiation devices.2 The concept of photoredox catalysis initially introduced by Nicewicz and MacMillan309 has been extended by Lalevée et al.310 for the formation of (TMS)3Si• and (TMS)3Si+ species. The catalytic cycle is depicted in Scheme 113. These new photoinitiated systems are based on a combination of photocatalyst (PC) [usually ruthenium or iridium complexes like tris(2,2′-bipyridine)ruthenium(II) dichloride hexahydrate ([Ru(bpy)3]Cl2•6H2O)

8.3. Free Radical-Promoted Cationic Polymerization (FRPCP)

The development of ring-opening polymerization reactions under conventional irradiation conditions (λ > 300 nm) is actually rather limited, unless a sensitization procedure is applied.285,291−293 Among the different approaches developed, the FRPCP is actually recognized as an interesting alternative for the use of longer wavelength.290 The FRPCP corresponds to the excitation of a photosensitive system (radical initiator) where a produced radical R• can be oxidized by diphenyliodonium salt (Ph2I+X−). The resulting cation R+ is the initiating species for the ring-opening polymerization. For a successful FRPCP process, the free radicals involved must be characterized by low oxidation potential for an efficient cation formation process, and the resulting cation must initiate the ring-opening polymerization (e.g., the ring opening of epoxides). (TMS)3SiH responds to such characteristics. The photoinitiated systems PI/TTMSS were sensitive upon visible light exposure and also under air, especially using diphenyliodonium hexafluorophosphate [Ph2I(PF6)]. There are several excellent recent reviews that describe the advancement of these protocols as well as the properties of polymers.287,288,291−293,302 These systems are very efficient for the polymerization of epoxy monomers.303 The general mechanism is given in Scheme 112. The *PI or R• abstract a H atom from TTMSS to give (TMS)3Si• radical. The oxidation rate constant (kox) of (TMS)3Si• by Ph2I+ was measured by laser flash photolysis and found to be kox = 2.6 × 106 M−1 s−1.304 The concomitant reduction of Ph2I+ leads to Ph• radicals that abstract hydrogen atom from (TMS)3SiH with a rate

Scheme 113. Possible Mechanism for Photoredox Catalysis Using (TMS)3SiH

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vinyl monomers such as methacrylate and styrene as well as to copolymerization. The polymerization-initiating properties of poly(hydrosilane)s, H-(RSiH)n-H [R = Ph, Si(CH2)3SiMe2Th, and c-Hex], were tested for free-radical photopolymerization (FRP) and free radical promoted cationic photopolymerization (FRPCP) (see section 8).323 Like TTMSS, these polymers are advantageous to overcome the classical oxygen inhibition.

and tris(2-phenylpyridine)iridium (Ir(ppy)3)], diphenyliodonium salt, and (TMS)3SiH.286,287

9. RADICAL CHEMISTRY OF POLY(HYDROSILANE)S The chemistry of poly(hydrosilane)s has not received much attention in the past decade. However, an overview of the subject is necessary because we believe that, like (TMS)3SiH, it can furnish an important scientific background for the development of silicon nanomaterials and functionalization of silicon surfaces, as summarized in the next two sections. Polysilanes have a silicon-catenated backbone with two substituents on each silicon atom.311 Polysilanes can be prepared by a number of procedures. There is the dehydrogenative coupling of RSiH3 in the presence of group 4 metallocenes to afford H-(RSiH)n-H (where R may be a variety of groups).312 A characteristic of this method is the presence in the products of Si−H moieties, which can exhibit a rich radical-based chemistry, much like TTMSS. The polysilanes of structure H-(PhSiH)n-H are stable to heating at 140 °C for a few hours. Whereas, they decompose to low molecular weight products with mainly cyclic structures in the presence of radical initiators.7 Furthermore, the oxidized products obtained when H-(PhSiH)n-H is exposed to air were identified, and kinetic studies were carried out in order to obtain mechanistic details of the processes.313,314 On the basis of these findings, a radical chain mechanism for H-(PhSiH)n-H oxidation was proposed by the reaction sequence that is similar to the mechanism for reaction of (TMS)3SiH with air oxygen (cf. Scheme 65). Poly(hydrosilane)s, when used as radical-based reducing agents for organic halides (R−X, with X = Cl, Br, or I), rival the effectiveness of (TMS)3SiH.315 Various monosubstituted olefins underwent addition to H-(PhSiH)n-H in refluxing toluene or 2,5-dimethyl-THF with the radical initiator AIBN.316 This resulted in the synthesis of functionalized polysilanes from addition of a silyl radical to the less-crowded position on the double bond with a high degree of substitution. Conversion of the Si−H groups ranged from 84% to 93%. The addition of olefins with polar side groups produced polysilanes that were soluble in alcohols and water. Poly(hydrosilane)s have been applied as stabilizers for the processing of organic polymeric materials to prevent oxidative degradation.317 Polyolefins can degrade significantly during processing via free radical mechanisms. Therefore, the ability [e.g., of poly(phenylhydrosilane)] to stabilize polypropylene during multiple extrusions was seen as an important finding. The protective effect of the polysilane is believed to be due to a combination of radical quenching by hydrogen donation, and the ability of the polysilane to scavenge any traces of oxygen present during extrusion. Moreover, incorporation of sterically hindered amine groups into the polysilane, via radical hydrosilylation of olefins or ketones, yielded polysilanes that could act as a stabilizer for the polyolefins during their lifetime.318 In this way, the free radical chemistry associated with poly(hydrosilane)s has been combined with well-known activity of HALS (hindered amines light stabilizer) to achieve a synergistic effect. More recently, a variety of new poly(hydrosilane)s were synthesized by the usual catalytic dehydrocoupling of the corresponding carbosilane monomers and used further in the hydrosilylation reaction to obtain polysilane-bearing functional groups for structural studies and investigation of optical properties.319−321 Poly(MMA)s grafted to H-(p-XPhSiH)n-H (where X = H, Me, MeO, F, Cl, and Br) were obtained by photopolymerization of MMA (methyl methacrylate) on poly(hydrosilane)s.322 This approach was extended to other

10. (TMS)3SiH IN THE SYNTHESIS OF NANOMATERIALS In this section, we considered the synthesis of nanomaterials that employed TTMSS as reducing agent in the metallic nanostructure synthesis like in the case of nanowires, or as a model for the functionalization of silicon nanocrystals similar to hydrogenterminated Si(111) surfaces (section 11). 10.1. Nanowires

Transparent conductors are indispensable in consumer electronics, and the majority of current technologies rely on indium tin oxide (ITO)-based thin films, which have high optical transparency and low electrical resistivity.324 ITO suffers from several drawbacks and several attempts have been reported, including metal nanowire network, to replace it as a transparent conductor. Copper is a good candidate for nanowire-based substitutes, and intense research has been devoted toward synthesizing long copper nanowires with small diameter. Yang and co-workers developed a novel synthetic approach using TTMSS as a mild reducing reagent to achieve ultrathin, uniform, and high-quality monodispersed copper nanowires, with an average diameter of 17.5 nm and a mean length of 17 μm.325 Summarizing the proposed mechanism: CuCl2 is initially converted to Cu(II) complex of oleylamine, then to a Cu(I) species at 100 °C, and then reduced further to Cu(0) at 150 °C via TTMSS; it is believed that the initially formed (TMS)3Si• radical can act as an electron donor and slowly reacts with the Cu(I) complex to produce Cu(0). Aside from acting solely as a reducing agent, TTMSS plays a key role in forming ultrathin nanowires: the mild reducing power of TTMSS affords sufficiently slow reduction rate to allow time for the nucleation of the nanoseeds and subsequent nanowire growth. Changing TTMSS and copper precursor concentration can modify the size of nanowires (e.g., nanowire diameter can be tuned from 15.5 to 22.5 nm when the molar ratio of TTMSS/CuCl2 decreases from 8 to 2). This work also demonstrated that TTMSS is a unique reducing reagent for metal nanomaterial synthesis, and this approach advanced research into the commercialization of copper nanowire mesh electrodes.325,326 The method was extended to the synthesis of ultrathin Cu@Au core−shell nanowires.327 Low-temperature silicon-containing nanowires remains a challenge in synthetic chemistry due to the lack of sufficiently reactive silicon (Si) precursors. Gallium-catalyzed colloidal Si nanowires were obtained using TTMSS as coreactant at temperatures of about 200 °C, which is more than 200 °C lower than that reported in the previous literature.328 The Et3Ga is the organometallic gallium precursor, and its thermal decomposition produces nanoscale gallium metal particles in the solution and ethyl radicals. The deleterious ethyl radicals are intercepted by TTMSS to generate (TMS)3Si• radicals. It is further believed that (TMS)3Si• radicals serve as the active species for silicon growth. Control experiments by replacement of (TMS)3SiH with (TMS)3SiCl or (TMS)4Si failed to grow Si nanowires, which further supports the proposed reaction 6555


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pathway. This development represents an important step toward low-temperature fabrication of Si nanowire-based devices for broad applications.328 The same research group in an international patent described methods using silane-based reducing agents, including (TMS)3SiH, to produce ultrathin metal nanowires and the use of the metal nanowires as transparent conductors.329

Scheme 115. Functionalization of H-SiNCs Surfaces with Alkenes in the Presence of XeF2 and Reaction of TTMSS with XeF2

10.2. Silicon Nanocrystal Surfaces

Silicon nanocrystals (SiNCs) have unique optoelectronic and chemical properties and developing versatile methods for tailoring particle surface chemistry to provide chemical stability is quite important.330 Hydrosilylation provides a wide range of surface functionalities and effective passivation of surface sites.331 In most cases hydrosilylation leads to enhanced light emission from SiNCs.331 Radical initiated hydrosilylation of hydrogenterminated silicon nanocrystal surfaces (403, H−SiNCs, d ∼ 3 nm) by terminal alkenes (i.e., 1-dodecene, 10-undecenoic acid, methyl-10-undecenoate, and styrene) and alkynes (1-octyne, phenylacetylene), using two common radical initiators (i.e., AIBN and benzoyl peroxide) or thermal conditions (125 °C), has been reported (Scheme 114).332 A typical AIBN-initiated

activated hydrosilylation of alkenes, alkynes, and ketones. Reactions of TTMSS as model of silicon surface with stoichiometric quantities of XeF2 provided six fluorosilanes as well as a number of oligosilanes, involving Si−Si bond cleavage and also new Si−Si bond formation (Scheme 115).334 Like the H−SiNCs surface activation, this reaction is fast. The mechanism of this process is quite complex involving radicals, radical ions, and probably silylenes.

Scheme 114. Radical-Based Hydrosilylation of H−SiNCs (3 nm) by Alkenes and Alkynes

10.3. Miscellaneous

The use of (TMS)3SiH as suitable radical-based reducing reagent for surface functionalization or formation of composite materials based on functionalized nanoparticles was reported.336,337 The specific embodiments of the invention are (i) facile functionalization of carbon nanotubes (single wall or multiwall), (ii) facile thiol functionalization of carbon nanomaterials, (iii) facile functionalization of tungsten, titanium or aluminum nanoparticles, and (iv) facile functionalization of polylactic acid.

reaction at 60 °C between H−SiNCs and 1-dodecene became transparent after ca. 5 h and the surface coverage of SiNCs functionalized with this alkene was 50% (402), whereas the surface coverage for phenylacetylene was 33% (404). The results indicated that the functionalization occurs and result in the formation of monolayer-passivated surfaces, with the reaction proceeding via a mechanism that begins with abstraction of a surface hydride, which is similar to what is reported for TTMSS. It is worth mentioning that surface functionalization of H− SiNCs with 1-dodecene via thermal hydrosilylation afforded dodecyl oligomers (n ≤ 4) in the temperature range 100−190 °C.333 In order to inhibit ligand oligomerization and obtain monolayer coverage on SiNC surfaces, it was suggested to apply comparatively low temperatures, inert atmosphere, and dilute ligand concentration during thermal hydrosilylation.333 A room-temperature method for functionalizing hydrideterminated H-SiNCs surfaces within seconds by stripping outermost atoms on the surfaces with xenon difluoride (XeF2) was reported (Scheme 115).334 The surface of SiNCs, like porous silicon (p-Si), is a complex mixture of Si−Hx (x = 1−3).335 It was shown that etching of SiNCs with XeF2 proceeds by elimination of fluorosilanes, HxSiFy (x + y = 4). This process led to the formation of transient surface silyl radicals that can be exploited to drive rapid reactions to produce functionalization surfaces (405). Existing methods for functionalizing H-SiNCs require a very long time (3−72 h), whereas this process is complete within seconds (30−60 s).334 Detailed analysis of the reaction byproducts by in situ NMR spectroscopy and GC/MS provided unprecedented insights into SiNCs surface composition and reactivity as well as into the complex reaction mechanism of XeF2

11. RADICAL CHEMISTRY ON HYDROGEN-TERMINATED SILICON SURFACES 11.1. Chemical Similitude Studies of H−S(111) and H−Si(100)-2 × 1 Surfaces with (TMS)3SiH

The properties of materials are dictated in large part by their surface functionality. Mechanistic understanding and control of silicon surfaces are of great importance for technological applications, since the fraction of atoms residing on or near the surface influence material properties.338 Indeed, the chemical termination of the surfaces of solids is well-known to dramatically influence electronic, chemical, and structural properties of the resulting materials.339 In the last two decades, much attention has been directed toward the synthesis of organic monolayers, which can be modified upon demand for specific requirements. For example, the assembly of biomolecules on silicon surfaces is of growing interest for applications in biochips and biomaterials. Currently, the methods for controlled surface modification are not as well developed synthetic methodologies in solution, such as the case for TTMSS in organic synthesis in comparison with hydrogen-terminated silicon surfaces. Methods available so far for preparing organic films on silicon surfaces include wet chemical, gas-phase, and ultrahigh vacuum approaches. Among the various chemical approaches, radical reactions are recognized as the most convenient method for achieving organic modifications of hydrogen-terminated silicon surfaces.340,341 As Buriak pointed out in her review,342 the reactions on silicon surfaces cannot be considered as exclusively molecular in any 6556


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was prepared by treating H−Si(111) with PCl5 in chlorobenzene under free radical conditions using thermal decomposition of dibenzoyl peroxide. The Cl−Si(111) was characterized by several spectroscopic methods and further used in reactions with organolithium or alkyl Grignard reagents to produce the R− Si(111) moieties. Analogously, H−Si(111) surfaces were brominated by reaction with N-bromosuccinimide or BrCCl3 to give Br−Si(111) using radical initiating conditions.350 Other methods of halogenation have also been used to obtain nominally the same X−Si(111) surface (X = Cl, Br, and I). Scheme 117 shows the schematic representation of halogen attachment onto silicon via surface-isolated silyl radical 406 that afforded, 407, 408, and 409 surfaces, respectively.351

sense, they fall into the category of true materials chemistry, and an extraordinary example is the photochemistry of silicon surface. In this section, we would like to report on the similarities of radical-based reactions of H−Si(111) surfaces and TTMSS, hoping that the experience made to develop synthetic methodologies in solution can be a source of inspiration for new reactions to get materials with peculiar properties. For specific subjects, the reader is guided to specialized reviews on the silicon surface modification and material chemistry.340−344 The section presents the reaction types analogous to those previously described for TTMSS. Structural properties of hydrogen-terminated silicon surfaces are of critical importance for their chemical behavior. Although the porous silicon (pSi) is terminated with SiH, SiH2, and SiH3 moieties in a variety of different local orientations and environments, the Si(111) and Si(100) are flat (single crystal) with specific orientations.341,342 Under ultrahigh vacuum conditions and exposure to hydrogen atoms, it is possible to produce from Si(100) the so-called H−Si(100)-2 × 1 dimer surface, in which the Si−H surface bonds decrease from two per silicon to only one (Scheme 116).340,345 These materials can be

Scheme 117. Halogenation of H−Si(111) Surfaces

Scheme 116. Hydrogen-Terminated Si(111) and Si(100)-2 × 1 Surfaces

prepared and manipulated in air for tens of minutes as well as in a number of organic solvents. However, by prolonged exposure to air, single crystal silicon becomes coated with a thin, native oxide that can be removed chemically from Si(111) using 40% aqueous NH4F or from Si(100) and porous silicon surfaces using dilute aqueous HF. The H−Si(111) and H−Si(100)-2 × 1 surfaces have twodimensional rhombic and square lattices, respectively. Surface sites array in an isotropic style on H−Si(111) but adopt the anisotropic distribution on H−Si(100)-2 × 1. These properties influence profoundly the various film structures and, consequently, the reaction outcome.346 Both H−S(111) and H− Si(100)-2 × 1 resemble (TMS)3SiH in a way that three silicon atoms are attached at the SiH moieties. Therefore, it is not surprising that several of (TMS)3SiH reactions have been adopted and applied to surfaces, and that mechanistic schemes are often proposed in analogy with (TMS)3SiH synthetic transformations. Despite some structural similarities, the H− Si(111) surface has a band gap of about 1.1 eV, while the HOMO−LUMO gap in the (TMS)3SiH is within 8−11 eV, which leads to significant consequences for the reactions with nucleophilic and electrophilic species.340

Insertion of dichlorocarbene (:CCl2), by the Seyferth reagent PhHgCCl2Br, into H−Si(111) surfaces produced surface-bound dichloromethyl groups (Si−CCl2H) covering ∼25% of the silicon surface sites, although all of the Si−H sites are consumed during the course of the functionalization.352 A significant fraction of the remaining Si−H bonds on the surface was converted to Si−Cl/Br groups during this process, emphasizing the important role of surface silyl radicals in dictating reaction outcomes on H−Si(111) surfaces. The Si−Cl/Br sites were reported to selectively react with sodium azide to form Si−N3 on the silicon surface.352 It is worth adding that the use of persistent aminocarbenes to functionalize H−Si(111) via Si−H insertion reactions and its comparison with TTMSS is reported.353 It was shown that among different classes of persistent carbenes, the more electrophilic and nucleophilic ones are able to undergo insertion into Si−H bonds at the silicon surface. The reaction of H−Si(111) surfaces with alcohols has no analogous molecular counterpart. In contrast, the H−Si(111) surface primarily undergoes a substitution reaction with alcohols, resulting in RO−Si(111) functionality on the surface.354 A mechanistic study of the oxidative reaction of H−Si(111) surfaces with liquid methanol has been reported.355 When H−Si(111) is exposed to 0.5 mM solution of an aryldiazonium salt in CH3CN in the dark, over 2 h under an inert atmosphere, it afforded the grafting of the aryl group onto the silicon surface and can also lead to the formation of closely packed surface-bound aryl layers.356,357 This method involves a one-electron reduction of the aryldiazonium salt to the corresponding aryl radical, which then combines with the

11.2. Replacement of Hydrogen-Terminated Si(111) Surfaces with Heteroatom Moieties

The radical-based functionalization of H−Si(111) surfaces with formation of Si−heteroatom is an area of intense and active investigations. Crystalline H−Si(111) surfaces have been alkylated in a two-step chlorination/alkylation process using a variety of alkyl groups, from methyl to sterically bulky substituents.339,347−349 In the first step, the Cl−Si(111) surface 6557


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surface-isolated silyl radical 411 to yield the surface-bound aryl 412 as shown in Scheme 118.356−358 It is worth mentioning that

directly on H−SI(111) surfaces 417 are shown in Scheme 119. By this protocol, immobilized aromatic groups with redox-active

Scheme 118. Aryldiazonium Salt Reacts Spontaneously with H−Si(111) under Different Reaction Conditions to Afford Modified Si(111) Surfaces

Scheme 119. Palladium-Catalyzed Arylation of TTMSS (Model Reaction) and Arylation of H−Si(111) Surface

and photoluminescent properties were obtained and further applied in the field of rigid π-conjugated redox molecular wire composites. 11.3. Hydrosilylation of Silicon Surfaces

Hydrosilylation of an alkene or alkyne is an ideal approach to produce covalent Si−C bonds between the silicon surface and organic molecules. Linford and Chidsey pioneered the preparation of monolayer films covalently bonded to silicon surfaces by radical-initiated reactions of terminal alkenes with H−Si(111) surfaces.364,365 The procedure employed neat deoxygenated alkenes initiated by radicals from the thermal decomposition of diacyl peroxides. The hydrosilylation could be achieved without radical initiation, either by heating at temperatures >150 °C or by UV irradiation. Spectroscopic data indicated densely packed monolayers with Si−C linkages. The modified surface, R−Si(111) (421), could withstand boiling water, boiling CHCl3 and sonication in CH2Cl2, indicating a chemisorption, rather than physisorption, of the monolayer onto the silicon.365 The mechanism originally proposed by Linford and Chidsey for surface hydrosilylation was based upon work done with TTMSS, the reaction formally being a hydrosilylation (Scheme 120).364,365 The initial surface-silyl radical 418 undergoes addition of the alkene, yielding a secondary alkyl radical 419 that then abstracts hydrogen from a vicinal Si−H bond, thereby regenerating a surface silyl radical 420. Each step in the sequence of radical translocations is an adduct carbon to the silicon surface via a 1,5-hydrogen shift (as is theoretically

the spontaneous one-electron reduction of diazonium salts on hydride-terminated flat silicon producing surface radicals is not observed in the chemistry of TTMSS. The difference in reactivity between the TTMSS and the surface is due to the fact that the silicon surface is a source of electrons to reduce the diazonium salts to aryl radicals.357 Using this initiation step, Buriak et al. investigated the radical chemistry of H−Si(111) surface with a range of organochalcogenide reagents (comprising S and Se).357,359 Scheme 118 shows the final products obtained by using RSSR or PhSSPh for the formation of RS−Si(111) and PhS−Si(111) (413) and PhSeSePh or PhSeR for the formation of PhSe−Si(111) (414). In analogy with the chemistry of TTMSS, a homolytic substitution at S or Se moieties is proposed. On the other hand, the reactions with chalcogenide ethers, butyl sulfide, diphenyl sulfide, and diphenyl selenide do not afford the surface modification. Interesting results were obtained with alkanethiols, which react with the surface under the protocol conditions and produce RS−Si(111) (413). A homolytic substitution at sulfur is suggested, although the possibility of direct coupling of RS• and surface radicals (411) cannot be ruled out, similarly to the Si−S bond formed between 1-dodecanethiol and H−Si(111) under ultraviolet-assisted photochemical reaction.360 More recently, the same group introduced a new protocol for the production of alkylS−Si(111), arylS−Si(111), and PhSe−Si(111) surfaces based on very fast microwave heating (10−15 s) or direct thermal heating (hot plate, 2 min), through the reaction of hydrogen-terminated silicon surfaces with dialkyl or diaryl dichalcogenides, extending to the tellurium derivatives PhTe−Si(111) (415).361 It is worth mentioning that applying the catalytic arylation reactions of TTMSS using Pd catalyst in homogeneous systems,362 the formation of clean organic monolayers with Si−Ar bonds on hydrogen-terminated silicon surfaces was developed.363 The model reaction of TTMSS affording compounds 416 and the analogous surface transformation affording the surface reaction to immobilize aromatic group

Scheme 120. Possible Mechanism of Alkene Addition to Hydrogen-Terminated Si(111) Surface

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supported).366 Supporting this picture is that when electrons from a scanning tunneling microscope were used to make surface-isolated silyl radicals on the Si(111) surface under ultrahigh vacuum, their exposure to styrene lead to formation of small islands of styrene adsorbates, bonded to the surface through individual C−Si bonds.366 The cluster-shaped aggregations of styrene molecules on H−Si(111) are produced by undirectional chain reactions along the isotropic hexagonal arrangement of surface sites; their formation adding support for the radical-chain mechanism of Scheme 120.366 Molecular monolayers may also be formed on H−Si(111) surfaces using a gas-phase photochemical method (with UV light from a mercury lamp). In this case, the monolayer can grow via either a radical-chain reaction mechanism or by direct radical attachment to dangling silicon bonds.367 The use of alkenes with αheteroatoms is reported to improve both surface coverage and the packing density of the monolayers as shown in Scheme 121 for silicon surface 422 by replacing CH2 with O or S.368

Scheme 122. Comparative Hydrosilylation of H−Si(111) Surface and TTMSS under Similar Conditions (Affording 51% Monolayer Coverage for RCN and 56% for R CO2CH2CF3)

conditions, UV irradiation, sonication, or electrochemistry. Recent reviews describe a number of proposed mechanisms.341−344 The search of ever milder and faster methods for coating the silicon surface has led to excellent protocols that can be accomplished at room temperature in the dark344,371,372 as well as with irradiation at 658 nm (white-light). Notably, Zuilhof and co-workers investigated the coating of H−Si(111) by alkenes and alkynes under irradiation with 658 nm (white) light. They suggested that holes created from excitons migrate to the surface forming delocalized radical cations (425).373 The radical cations are subsequently attacked at the surface by nucleophiles fragmenting 425 into cation + radical pairs that add to the alkene to afford 426. The β-silyl alkyl radical moiety of 426 then abstracts hydrogen atom from a neighboring Si−H site, leaving the radical on the silicon surface (427) (Scheme 123). This

Scheme 121. Modification of H−Si(111) Surface by Hydrosilylation Process

Monolayers may also be formed on H−Si(111) using terminal acetylenes, such as 1-octyne or phenylacetylene, with radical initiation from diacyl peroxide thermolyis or UV photolysis.345,365 There is spectroscopic evidence that the vinyl group is covalently attached to the Si surface. As previously with alkenes, the mechanism for alkynes includes a surface propagation chain reaction in which a vinyl radical, formed by the addition of alkyne to a surface silyl radical, abstracts a hydrogen atom from an adjacent site of the polysilane chain. Modification of H−Si(111) surfaces by hydrosilylation of activated alkenes and alkynes is comparable to hydrosilylation by (TMS)3SiH under milder conditions.369,370 Thus, when H−Si(111) surfaces were freshly prepared and then treated with neat alkene or alkyne, or when (TMS)3SiH is mixed with neat alkene or alkyne, the hydrosilylation proceeds smoothly at ambient temperature under room lighting. The fact that similar results were obtained in the dark suggests radical initiation in both systems was due to silane reaction with traces of molecular oxygen (vide infra). Polysilane surface coverage by the organic monolayer 423 was estimated by X-ray photoelectron spectroscopy analysis to be 16−58% for alkenes and 51−56% for alkynes, whereas the corresponding reaction with (TMS)3SiH gave 424 in yields of 50−87% for the alkenes and 75−94% for the tested alkynes. Two examples are reported in Scheme 122. Theoretical calculations at the B3LYP/ 6-31G*//HF/STO-3G* level indicated the Si−H bond dissociation energies of H−Si(111) and (TMS)3Si−H were nearly identical, which supports the use of the well-established radical-based reactivity of (TMS)3SiH as a theoretical and practical model for surface reactions.369 A substantial number of radical-initiated hydrosilylations by H-terminated Si(111) surfaces of terminal alkenes and alkynes have been reported. Most were performed under thermal

Scheme 123. Monolayer Formation onto H−Si(111) Surface Initiated by Visible Light

initiates a radical chain reaction which then propagates (427 to 428) in a similar fashion to the mechanism described above (see 420 in Scheme 120). A variety of functionalized H−Si(111) surfaces have been synthesized by this method; surfaces coated with alkenes,368,373 alkynes,349,373,374 and alkyl silanols.375 Mixed monolayers made from the mixtures of pairs of alkenes were also investigated, revealing that the composition of the mixed 6559


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Scheme 124. Possible Mechanism of Radical Chain Reaction of the Growth of Styrene Line along the Edge of the Dimer Rows on the H−Si(100)-2 × 1 Surface

reaction can be directed either along or across the dimer rows on the surface of H−Si(100)-2 × 1. The strong directionality is due to the H−Si(100)-2 × 1 anisotropic type. The direction of growth depends on the degree of delocalization in the carbon radicals, on nonbonding forces between the alkyl chains and the surface, and on the distance between the intermediate radical center and the anchoring point to the silane chain.376,380 When this alkene-hydrosilylation methodology for H− Si(100)-2 × 1 surface was extended to aldehydes and ketones, the derived nanostructures were bound to the surface by strong Si−O covalent bonds.381 With the aldehydes, benzaldehyde and acetaldehyde, the resulting organic-silicon nanostructures were directed along both single and double lines of attached molecules, indicating that the intermediate carbon radicals reach and abstract both the nearest H atom in the same row and the H atom of the adjacent row. Acetone, on the other hand, undergoes a chain reaction resulting in only single molecular lines, with molecules bonded to one of the Si−Si dimer atoms lying on the same side of a row (i.e., there is no crossing over between the dimer chains).382 Cyclopropyl methyl ketone, by contrast, reacted at single dangling bonds forming a cyclopropylmethyl adduct, that underwent ring-opening prior to hydrogen abstraction from one of the various surface SiH groups within the range of the radical.383 This addition-ring-openingabstraction process was then repeated, leading to a continuous string of molecules attached to the surface. Ultrahigh-vacuum STM has been used to examine the addition of the TEMPO radical (2,2,6,6-tetramethyl-1-piperidinyloxyl) to the dangling bond of the Si(100)-2 × 1 surface.384,385 Although TEMPO might be expected to couple with a single dangling bond to yield stable Si−O-bonded products, the TEMPO molecules were easily removed from the surface, perhaps due to lability of the (Si)O−N bonds.

monolayers was directly proportional to the concentrations (i.e., molar ratios) of the two compounds in solution. The radical cation-initiated reaction mechanism has been investigated using (TMS)3SiH as a kinetic-analysis benchmark.289 That is to say, (TMS)3SiH and its branched analogous 429 were used as model compounds for studies and better understanding the one-electron oxidation. The oxidation potential of TTMSS and 429 are 1.67 and 1.42 V, respectively. The corresponding radical cations, resulting from photoinduced electron transfer, react readily with a variety of nucleophiles regularly used in monolayer fabrication onto H−Si(111). Rate constants (k, × 106 M−1 s−1) for reaction of 429+• with 1-decene, 1-decyne, 1-undecanol, and water are 1.7, 3.5, 25, and 33, respectively. The combination of product yield data and the kinetic data indicated a bimolecular mechanism with Si−Si bond cleavage and only a small amount of spontaneous radical cations fragmentation.

Unlike the island or cluster distributions observed with H− Si(111), the addition of alkenes to H−Si(100)-2 × 1 surfaces yielded coatings with one-dimensional lines of molecules along the Si−C linkages.376 Thus, when reaction was initiated by isolated surface silyl radicals (made by the tip of the scanning tunneling microscope, STM), the STM images revealed lines of molecules running along and across the dimer rows according to the structure of R in the alkene, CH2CH−R. For example, the surface silyl radical 430 added to the CC double bond of styrene, forming a carbon-centered radical, which translocates on the surface via a 1,5-hydrogen shift within the same row to produce silyl radical 431 (Scheme 124).376 The new silicon radical center then accepts another styrene molecule, leading to the reaction along the dimer rows (432). Preferential growth along one edge of a silicon dimer has also been observed with long-chain alkenes (R = CnH2n, n ≥ 8).377 With an allyl mercaptan, on the other hand, the line of surface-bonded molecules grows across the rows.378 In this case, the initial carbon radical is thought to rearrange to a sulfur-centered radical in a 1,3hydrogen shift that is followed by radical translocation from sulfur to the silicon surface on the neighboring row. H-atom abstraction from the neighboring row results in a surface silicon radical that adds to an allyl mercaptan molecule leading (in repetition) to the observed cross-row chain reaction. These cross-row lines are stable even up to 659 K.379 Similarly, trimethylene sulfide also produces structures that grow along dimer rows.380 Here it was proposed that the silyl radicals on the surface attack the trimethylene sulfide at the sulfur, producing a new Si−S bond and a carbon-centered radical via ring-opening. Thus, by varying R in the alkene CH2CH−R, the chain

11.4. Oxidation of Hydrogen-Terminated Silicon Surfaces

H−Si(111) surfaces develop oxides on the monolayer after sitting, on average, for 1 h in typical air and lighting room conditions. The oxidation occurs when the surfaces are exposed to UV light in the presence of dry or humid air.345,386 The area of the νSi−H band in the FTIR spectrum of H−Si(111) decreases to 14% after 30 min under Hg lamp illumination.345 The surface oxidizes under UV light in the presence of O2 only, H2O only, or humid air (both O2 and H2O).386 Under dry air, the surfaces oxidize in UV-light ten times more than when they are exposed to either 447 nm wavelength or no light. It has been proposed that UV light assists oxidation by cleaving the H−Si surface bond because photon-stimulated hydrogen desorption occurs around 351 nm, corresponding to the energy required to dissociate the H−Si bond. Both surfaces are oxidized when exposed to moisture (H2O) and UV light. Photo-oxidation of silicon surfaces under UV light is about 10-fold faster in humid air than in dry air or in water. It has been proposed that H2O and/or 6560


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HOO•, corresponding to the reaction of O2 with (Me3Si)3SiH, have been reported.369,392

O2 scavenge the UV-generated silicon radicals to produce the siloxane surface. The mechanism of silicon-surface photooxidation is not well -understood. One hypothesis is that the surface silyl radicals, 433, formed by UV irradiation of H−Si(111), react with O2 to produce a peroxyl radical 434 that then abstracts a neighboring hydrogen to produce a new surface dangling O−H bond and silyl radical 435 (Scheme 125).345,386 How oxygen migrates into the

12. CONCLUSIONS AND OUTLOOK The discovery of a new reagent plays an important role in the development of organic chemistry, and tris(trimethylsilyl)silane offers a good example of how a multidisciplinary approach can yield diverse and productive results. For example, studies of the thermodynamic and kinetic features of TTMSS influenced the planning of synthetic schemes. The molecular properties of this reagent, including its solvent compatibility, environmental inertness, and ease of workup, address the many needs of organic synthetic chemists, especially when the process has to be scaled-up. Its nontoxicity further enhances the value of this reagent and renders it unique for use in medicinal chemistry. All of these aspects were highlighted in this review, and together they certainly explain the widespread application of TTMSS, herein reviewed primarily with regard to the past decade. The use of TTMSS has been investigated on a variety of methodologies and synthetic processes, from functional group transformations to natural product synthesis and materials development. Cheves Walling wrote in his autobiography, Fifty Years of Free Radicals: “Free radical chemistry [···] has grown from very modest beginnings to become a major part of organic chemistry [and] impinges widely on many other areas of chemistry”.393 The same can be said of tris(trimethylsilyl)silane at its 30 year anniversary, and we foresee decades of development of TTMSS as a crucial reagent for chemical transformations using free radical chemistry for both academic and industrial chemists well into the future.

Scheme 125. Possible Mechanism for the Oxidation of a Silicon Surface by Molecular Oxygen

Si−Si lattice and how the surface silyl radical is regenerated and a new Si−H bond arises has not yet been established. The mechanism depicted in Scheme 125 was first proposed by Chatgilialoglu7 based on corresponding oxidation mechanisms for (TMS)3Si−H and poly(hydrosilane)s.165 Rearrangement of peroxyl radical 434 affords silyloxyl radical 436 in an oxygen insertion step that has a rate constant of ∼104 s−1 in the analogous reaction in (TMS)3Si−H. The alternative direct hydrogen abstraction by the silylperoxyl 434 to afford 435 is expected to be far slower since, for example, the analogous bimolecular H-abstraction (Me3Si)3Si−H by cumylperoxyl radical has a rate constant of only 66 M−1 s−1 at 73 °C. In contrast, the second step of oxygen insersion, radical 436 is a rapid 1,2-silyl shift to give silyl radical 437, which couples to oxygen and so on with the remaining Si−Si bonds. Alternatively, radical 436 could abstract a neighboring hydrogen to generate another surface silyl radical (438) and so on, eventually until there is complete oxidation of the surface. It is likely that the preferred path will strongly depend on the oxygen concentration and entropic factors determined by the rigidity of the surface. This mechanism is consistent with the various spectroscopic data showing evidence for peroxyl radical species on the silicon surface during thermal oxidation,387 and it is consistent with theoretical considerations.388 Infrared-absorption data and firstprinciples quantum chemical calculations both indicate that the initial oxidation of clean H−Si(100)-(2 × 1) surface by O2 involves the formation of a metastable silanone intermediate, (O)SiO, containing two oxygen atoms, presumably from the same O2 molecule.389 Oxidation of hydrogen-terminated silicon surfaces by O2 may also occur in the dark. The STM investigation indicated exposure of H−Si(111) to O2 induced surface modification consistent with insertion of oxygen atoms into the Si−Si backbone.390 Photo-oxidation is fastest when the surface is exposed to both O2 and H2O in the presence of UV light.391 Evidence supporting a spontaneous reaction of O2 with H-terminated silicon surfaces to afford surface radicals and

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. ORCID

Chryssostomos Chatgilialoglu: 0000-0003-2626-2925 Yannick Landais: 0000-0001-6848-6703 Notes

The authors declare no competing financial interest. Biographies Chryssostomos Chatgilialoglu was born in Nikea (Greece) in 1952. He received a doctorate degree in chemistry from the University of Bologna in 1976 and completed his postdoctoral studies at York University (UK) and the National Research Council of Ottawa, Canada. In 1983, he joined the Consiglio Nazionale delle Ricerche in Bologna (Italy), where he has been Research Director since 1991. From March 2014 to May 2016, he was appointed as the Director of the Institute of Nanoscience and Nanotechnology at the NCSR “Demokritos” in Athens (Greece). He introduced tris(trimethylsilyl)silane (TTMSS) as radical-based reducing agent, and for this achievement, he was the winner of the Fluka Prize “Reagent of the Year 1990”. His research interests lie in free radical reactions and in the past decade have been increasingly addressed to applications in life sciences. He is the author and editor of several books, including the Encyclopedia of Radicals in Chemistry, Biology and Materials published by Wiley in 2012. He is the author or coauthor of over 300 papers. He chaired the COST Actions CM0603 on Free Radicals in Chemical Biology (2007−2011) and CM1201 on Biomimetic Radical Chemistry (2012−2016). He is Co-Founder and President of the spin-off company Lipinutragen. 6561


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HAT HE HIV HOMO HR-MAS ITO LED LUMO MMA NMP PC PET PI PS PVDF SET SiNCs SRAA STM TBAF TBDMS TEMPO THF TPMA TTMSS UV V-70 Xc

Carla Ferreri started her scientific career in synthetic organic chemistry, being appointed as research fellow at the University of Napoli “Federico II” in 1984. In 2001, she moved to the Consiglio Nazionale delle Ricerche in Bologna, where she is currently Senior Researcher. Her present research interests are in the field of biomimetic chemistry, investigating free radical transformations of biomolecules related to the molecular pathways of radical stress, and in the transfer of basic mechanisms to biomarker discovery and health applications. She is cofounder of the spin-off company Lipinutragen and leads the R&D in nutrilipidomics and nutraceuticals. Yannick Landais was born in Angers (France) in 1962. He received his Ph.D. in chemistry in 1988 from the University of Orsay (Paris XI) under the supervision of Dr. Jean-Pierre Robin. After carrying out postdoctoral work with Prof. Ian Fleming at the University of Cambridge (1988−90), he joined the University of Lausanne to start his independent career. Since 1997, he has been professor of organic chemistry at the University of Bordeaux. His research interests are in synthetic organic chemistry, asymmetric synthesis, and radical and organosilicon chemistry. Vitaliy I. Timokhin was raised in Kramatorsk (Ukraine). He was an undergraduate and a graduate student at the Donetsk State University (Ukraine, Ph.D., 1978), where he worked with Professors Roman Kucher and Iosyp Opeida. He joined as a Senior Scientist at the Physical Chemistry Institute (Ukraine, 1983−2000), where his research group specialized in oxidation catalysis, with an emphasis on kinetics and mechanism of radical processes. He was a postdoctoral fellow and visiting scientist with Professors Chryssostomos Chatgilialoglu (Italy), Evgeny Denisov (Russia), Michele Bertrand (France), Santiago Esplugas (Spain), Shannon Stahl (USA), Robert West (USA), Daesung Lee (USA), Igor Alabugin (USA), and Jennifer Schomaker (USA). He is currently an Assistant Scientist with Professor John Ralph at the University of Wisconsin-Madison (USA). His research interests are in synthetic organic chemistry, radical chemistry, and development of economic processes for the production of bioproducts from biomass.

hydrogen atom transfer Hantzsch ester human immunodeficiency virus highest occupied molecular orbital high-resolution magic-angle spinning indium tin oxide light-emitting diode lowest unoccupied molecular orbital methyl methacrylate N-methyl-2-pyrrolidone photoredox catalysis photoinduced electron transfer photoinitiated polystyrene poly(vinylidenefluoride) single electron transfer silicon nanocrystals silane radical atom abstraction scanning tunneling microscopy tetra-n-butylammonium fluoride tert-butyldimethylsilyl 2,2,6,6-tetramethylpiperidine-1-oxyl tetrahydrofuran tris(2-pyridylmethyl)amine tris(trimethylsilyl)silane ultraviolet azobis(2,4-dimethyl-4-methoxyvaleronitrile) coupling efficiency

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DEDICATION We dedicate this work to the memory of our friend Evgeny T. Denisov (1930−2017), author of the original studies and publications in the field of kinetics and mechanism of radical processes. ABBREVIATIONS ACCN azobis(cyclohexanecarbonitrile) AIBN azobis(isobutyronitrile) ATRC atom transfer radical coupling BDE bond dissociation energy BHT 2,6-di-tert-butyl-4-methylphenol CFL compact fluorescent lamp DIPEA N,N-diisopropylethylamine DLP dilauroyl peroxide DMDC dimethyl dicarbonate DMF N,N-dimethylformamide DME 1,2-dimethoxyethane DNA deoxyribonucleic acid dr diastereomeric ratio DTBHN di-tert-butyl hyponitrite EDA electron donor−acceptor ee enantiomeric excess FRP free-radical polymerization FRPCP free radical promoted cationic polymerization FTIR Fourier-transformed infrared spectroscopy HALS hindered amine light stabilizers 6562


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