==== Front Chem Rev Chem Rev cr chreay Chemical Reviews 0009-2665 1520-6890 American Chemical Society 32786620-30-0856/acs.chemrev.0c00278 Review Generation of Alkyl Radicals: From the Tyranny of Tin to the Photon Democracy Crespi Stefano † Fagnoni Maurizio *‡ † Stratingh Institute for Chemistry, Center for Systems Chemistry University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands ‡ PhotoGreen Lab, Department of Chemistry, V. Le Taramelli 10, 27100 Pavia, Italy * Email: psims@example.net. Tel: 636.721.3155. Fax: 636.721.3155. 06 08 2020 09 09 2020 620-30-08569833 08 04 2020 2020 American Chemical Society Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/). Alkyl radicals are key intermediates in organic synthesis. Their classic generation from alkyl halides has a severe drawback due to the employment of toxic tin hydrides to the point that "flight from the tyranny of tin" in radical processes was considered for a long time an unavoidable issue. This review summarizes the main alternative approaches for the generation of unstabilized alkyl radicals, using photons as traceless promoters. The recent development in photochemical and photocatalyzed processes enabled the discovery of a plethora of new alkyl radical precursors, opening the world of radical chemistry to a broader community, thus allowing a new era of photon democracy. document-id-old-9cr0c00278 document-id-new-14cr0c00278 ccc-price ==== Body 1 Introduction Among all the open-shell species, carbon-centered radicals are intriguing neutral intermediates that find extensive use in organic synthesis, despite the initial distrust about their possible application.1−5 In particular, the generation of unstabilized alkyl radicals under mild conditions granting the controlled and selective outcome of the ensuing reactions has been a challenge for many years. The first and more obvious way to form such species is the homolytic cleavage of a labile C–X bond; alkyl halides appeared as the ideal choice in this respect. The real breakthrough in radical chemistry was the discovery of Bu3SnH to promote radical chain reactions as reported about 60 years ago in the reduction of bromocyclohexane.6 Reduction of an organotin halide by lithium aluminum hydride formed the reactive tin hydride in solution. In subsequent modifications of the protocol, both sodium borohydride7 and sodium cyanoborohydride8 acted as effective reducing agents. Alkyl radicals generated via tin chemistry were then used for C–C bond formation mainly via the addition to (electron-poor) olefins, the well-known Giese reaction,9−12 an evolution of the original process which made use of organomercury compounds.12,13 As illustrated in Figure 1a, tributyltin hydride has the double role of allowing the formation of Bu3Sn• as the radical chain carrier and as a hydrogen donor to close the catalytic cycle. The unique features of this catalytic cycle are attributed to the forging of stronger Sn–X and C–H bonds at the expense of the cleavage of the more labile Sn–H and C–X ones. A more quantitative aspect of this reaction can be appreciated comparing the different bond dissociation energies (BDE) associated with the steps mentioned above (see Figure 1a).14,15 More recent applications showcase the crucial role of tin intermediates in controlling the outcome of different reactions. Sn–O interactions direct the regioselective addition of the radical in the radical stannylation of the triple bond in propargyloxy derivatives,16 whereas tin radicals induced the synthesis of stannylated polyarenes via double radical peri-annulations, increasing the solubility of the products.17 Figure 1 (A) Thermal generation of radicals from alkyl halides in the Giese reaction. (B) LD50 values for selected organotin compounds. (C) Thermal generation of radicals from alcohols via xanthates (I). (D) Thermal and photochemical generation of radicals from carboxylic acids via Barton esters (II). The performance of Bu3SnH was so competitive9,18−20 that more than 20 years ago it was claimed that it was improbable to have "flight from the tyranny of tin" in radical processes,21,22 a hard statement that subtly introduces the problem of the substantial toxicity and high biological activity of triorganotin compounds.23 The LD50 of 0.7 mmol/kg in murine species (see Figure 1b) combined with the long half-lives in aquatic environment represent the biggest concerns for the application of these otherwise extremely versatile species, especially in the absence of viable alternatives.24 Indeed, O-thiocarbonyl derivatives like xanthates (I, obtained from alcohols) were considered an alternative to the alkyl halides, albeit the radical generation required in most cases the use of tin hydrides (Figure 1c).3,22,25,26 Efforts in substituting toxic tin derivatives with other hydrides such as (TMS)3SiH27 or lauroyl peroxides and xanthates met some success, however, only in limited cases.28−30 Other initiators to promote tin-free radical chain reactions were organoboranes,31 thiols,32 P–H-based reagents,32 and 1-functionalized cyclohexa-2,5-dienes,32−34 but nowadays they are not commonly used in synthetic planning. The use of metal oxidants (MnIII acetate)35 or metal reductants (TiIII catalyst36 or SmII iodide37) were sparsely used, but only in the latter case unstabilized alkyl radicals were formed from alkyl iodides. The introduction of the Barton esters II in 1985 represented a step forward in solving the conundrum of the tyranny of tin: the conversion of the strong O–H bond of an acid into the (photo)labile O–N bond of the corresponding thiohydroxamate ester (Figure 1d).38,39 Barton esters have the advantage of being slightly colored, allowing the use of visible light irradiation to induce the cleavage of the O–N bond. The last point is significant, demonstrating the formation of alkyl radicals in a very mild way under tin-free conditions with no need of further additives, albeit Barton esters have currently a limited application. On this occasion, photochemistry showed an attractive potential for the development of novel synthetic strategies based on radical chemistry. However, Barton esters remained for several years an isolated niche. In most cases, the photochemical generation of radicals required harmful UV radiation and dedicated equipment.40 Since the milestone represented by the development of the chemistry of Barton esters, new photochemical ways were sought toward more efficient ways to generate radicals. The photon appears to be the ideal component for a chemical reaction, assuming the form of a traceless reagent, catalyst, or promoter that leaves no toxic residues in the final mixture.41−44 The breakthrough that would allow moving forward from the "tyranny of tin" to a greener "photon democracy" can be associated with the use of solar or visible photons, freely available from the sun that shines throughout the scientific world. The renaissance of the photocatalyzed processes that we have witnessed in the last years represents a significant step toward this direction.45−58 The multifaceted use of photoredox catalysis and photocatalyzed hydrogen transfer reactions expanded the range of possible radical precursors and unconventional routes for the generation of several carbon (or heteroatom based) radicals, including the challenging formation of unstabilized alkyl radicals.59−65 Consequently, in this review, we aim to present a summary of the novel ways to generate alkyl radicals by photochemical means that, in the last years66 have revolutionized the way to carry out radical chemistry. This work will focus exclusively on the reactions promoting the formation of unstabilized alkyl radicals, and not the stabilized ones, e.g., α-oxy, α-amino, benzylic, or allylic. Figure 2 collects the main paradigmatic approaches to the photogeneration of alkyl radicals (either photochemically or photocatalyzed). The more classical, although the less employed, path to generate alkyl radicals consists of the introduction of a photoauxiliary group which renders a bond labile to a direct photochemical cleavage (Figure 2A).67 The Barton esters are the archetypal moiety belonging to this class.39 A conspicuous body of literature have been focusing on the development of suitable alkyl substituents able to facilitate redox reactions making the derivatives more oxidizable or reducible. The strategy that is followed in Figure 2B consists in the conversion of a common functional group (e.g., OH or COOH), which in most cases is tethered to the alkyl group, into a different electroauxiliary group68 (Figure 2B). As a result, the interaction of the activated species with an excited photoredox catalyst (PCSET) able to induce a single electron transfer (SET) process generates the corresponding radical ions, either by an oxidative pathway or a reductive pathway. The desired alkyl radical is then formed by fragmentation of these radical ion intermediates. The oxidative pathway is efficient when the radical precursor is negatively charged (see further Figure 3) as in the case of alkyl carboxylates and alkyl sulfinates causing the CO2 or SO2 loss, respectively, despite the fact that the exothermicity of the process is verified only in the C–C cleavage rather than the C–S cleavage.69 On the contrary, positively charged Katritzky salts were ideal candidates for the releasing of radicals via the reductive pathway (Figure 3).70 Figure 2 Different approaches for the photogeneration of alkyl radicals (A) by photochemical means through the introduction of a photoauxiliary group (B) via fragmentation of a radical cation (oxidative pathway) or anion (reductive pathway) formed by photoredox catalysis (C) via a halogen atom transfer reaction (XAT) with a photogenerated radical (D) through the photocatalyzed cleavage of a C–H bond via direct (d-HAT) or indirect (i-HAT) hydrogen atom transfer (E) by the remote-controlled C–H activation via a photogenerated heteroatom based radical (F) by a ring-opening via a photogenerated heteroatom (nitrogen) based radical. Figure 3 On the left, substrates used to promote the photochemical formation of alkyl radicals divided according to the C–Y bond cleaved. The oxidation potentials (Eox, in orange) or the reduction potentials (Ered, in green) of the precursors as well as the BDE values of the bond that is broken (highlighted in gray) by direct photocleavage are reported. On the right, a selection of common photoredox catalysts with their main redox features are collected. A viable alternative is the photogeneration (often from a photoredox process) of a reactive radical on a heteroatom like a silyl radical, which can exploit a halogen atom transfer reaction to afford an alkyl radical through the smooth Si-X bond formation (XAT, Figure 2C).71,72 This strategy provides an elegant way to overcome the Giese conditions in the tin mediated activation of alkyl halides. Recently, an α-amino radical was used in the same strategy, promoting the formation of alkyl radicals via C–X bond cleavage.73 A more challenging approach requires the photocatalyzed selective cleavage of a strong alkyl-H bond, via a direct hydrogen atom transfer reaction (d-HAT, Figure 2D) operated by an excited photocatalyst (PCHAT).72,74−76 The indirect version of the latter path exploits the photogeneration of a stable heteroatom based radical (i-HAT, Figure 2D) that will become the competent intermediate in the abstraction of the H atom from the alkyl moiety.76 An indirect HAT (i-HAT) may also take place by intramolecular hydrogen transfer thus releasing an alkyl radical (Figure 2E).76−81 As an alternative, the photochemical radical generation may induce a ring-opening in strained structures like cyclobutanes, to form a substituted alkyl radical (Figure 2F).82 Figure 3 showcases a collection of the main alkyl radical precursors devised for the generation under photochemical conditions of unstabilized alkyl radicals. In this figure, the radical precursors were collected depending on the C(sp3)-Y bond cleaved during the radical release. As apparent, the photochemically triggered cleavage of several C-heteroatom bonds like C–X,71,83−88 C–O,89−98 C–B,99−102 C–S,103−106 or C–N70 (Figure 3) affords carbon-centered radicals. The alkyl radical generation is granted by the very versatile photochemical tool. This feature includes particular cases such as C–Se (in alkyl selenides),107,108 C–Te [in (aryltelluro)formates,109,110 for a previous thermal generation of alkyl radical from diorganyl tellurides, see ref (111)], and C–Si (in tetra alkyl silanes and bis-chatecolates)112−114 to be added to C–Sn (in alkyl stannanes).112,115 Interestingly, even the more resilient C–H15,76 or C–C38,83,94,116−130 bonds may be cleaved for alkyl radical generation, opening up new exciting possibilities for the synthetic (photo)chemist (Figure 3). For the clarity of the reader, each radical precursor is accompanied by its oxidation potential (EOX, in orange) or its reduction potential (ERED, in green) to guide the feasibility on the generation of the radical via the oxidative or reductive pathway (type B, Figure 2B), respectively. Since the redox potentials may vary with the nature of the alkyl group, the values reported are referred to known structures. In alternative, the BDE values of the bond that is broken by direct photocleavage (type A, Figure 2A) or by photocatalyzed hydrogen abstraction (type D, Figure 2D) are reported. Figure 3 (right part) likewise collects the redox properties of commonly used photoredox catalysts including metal-free photoorganocatalysts (POC) to be used in the oxidative/reductive pathways.131−137 The reactions collected and commented on in this review are primarily divided according to the type of the bond formed, namely the forging of C–C or C–heteroatom bonds, along with the construction of rings of different sizes. When possible, in each section, we will further categorize the reactions depending on the mechanism of the radical generation, ascribing them to the six types (A–F) described in Figure 2. 2 Formation of a C(sp3)-C Bond Photochemically generated alkyl radicals have been employed to forge C(sp3)-C(spn) bonds (n = 1–3) in an intermolecular fashion following different strategies. In most cases, a conjugate addition onto a Michael acceptor or a Minisci-like reaction occurred, albeit alkenylations, acylations, or oxyalkylations are likewise used. 2.1 Formation of a C(sp3)-C(sp3) Bond 2.1.1 Addition to C–C Double Bonds: Hydroalkylations Many reactions belonging to this class involve the nucleophilic alkyl radical addition onto an electrophilic Michael acceptor, resulting in a formal hydroalkylation of the double bond viz. the incorporation of an alkyl group (in position β with respect to the EWG group in the starting unsaturated compound) and a hydrogen atom (in position α). This reaction is usually one of the first that many authors would test during the discovery process of a new radical precursor, as testified by the plethora of reagents that are used in this transformation. Photoredox catalysis is by far the preferred approach here, especially by using the oxidation of a negatively charged precursor (oxidative pathway in Figure 2B). A typical example is the oxidation of carboxylates138,139 that releases an alkyl radical via CO2 loss from the carboxyl radical intermediate (Scheme 1). Adamantylation of both acrylonitrile (Scheme 1a)140 and dimethyl 2-ethylidenemalonate starting from adamantane carboxylic acid 1-1 (Scheme 1b)141 were carried out following this strategy. In the former case, the authors employed 1,4-dicyanonaphthalene (DCN) as the POC under UV light irradiation, while visible light and an IrIII complex in the latter case. The approach used in Scheme 1b was also useful for the three steps preparation of the medicinal agent (±)-pregabalin.141 Also, the Fukuzumi catalyst (9-mesitylene-10-methylacridinium perchlorate, [Acr+Mes]ClO4) can promote this Giese-type reaction,142 allowing the alkylation of α-aryl ethenylphosphonates for the synthesis of fosmidomycin analogues.143 Scheme 1 Different Strategies for the Decarboxylative Adamantylation of Electron-Poor Alkenes A variation of this procedure is the decarboxylative-decarbonylative process occurring on an α-keto acid 2-1 under sunlight-driven photoredox catalyzed reaction conditions (Scheme 2).125 Scheme 2 Decarboxylative-Decarbonylation of an α-Keto Acid Oxalates are another class of electron-donors having two carboxylate moieties that can be lost upon photocatalyzed oxidation. These species may be introduced in situ by reaction of the alcohol with oxalyl chloride. The process induced the cleavage of a C–O bond, and the resulting radical could be trapped by butenolide 3–1 to form the menthyl derivative 3–2 used for the enantioselective preparation of cheloviolene A (3–3, Scheme 3).144 An IrIII-based photocatalyst efficiently promoted the reaction also in this case, allowing the synthesis of quaternary centers89 and the total synthesis of trans-clerodane diterpenoids.145 Scheme 3 Enantioselective Preparation of Cheloviolene A Alkyl trifluoroborates stand out as another important class of easily oxidizable moieties.146 The photocatalyzed oxidation of these salts (e.g., 4–1) causes the smooth release of BF3 and the formation of the reactive alkyl radical. Such a reaction was employed to functionalize Michael acceptors under sunlight irradiation (Scheme 4a) exploiting Acr+Mes as the POC.147 Complexation of 4–4 by a chiral rhodium complex (Λ-RhS, Scheme 4b) delivered 4–5 in good yields with 97% ee.148 Scheme 4 Visible and Solar Light Photocatalyzed Functionalization of Michael Acceptors with Alkyl Trifluoroborate Salts This synthetic strategy can be extended to neutral boronic acids or esters, upon in situ activation by a Lewis base (LB). The so formed negatively charged species is consequently more prone to oxidation, which eventually will provide the formation of the alkyl radicals. A typical example is illustrated in Scheme 5 where the boronic acid 5–1 was activated by 4-dimethylaminopyridine (DMAP) and then oxidized by an IrIII complex. The resulting cyclobutyl radical was trapped by methyl vinyl ketone to access the substituted ketone 5–2 in a good yield.100 This reaction was later scaled up under flow conditions by using the Photosyn reactor. In such a way, the authors could synthesize gram amounts per hour of the analogues of some drugs belonging to the GABA family.149 Scheme 5 Activation of Boronic Acids with a Lewis Base Following the examples of the carboxylate derivatives, the electron-donating species may be generated in situ by deprotonation, as in the case of sulfonamides, employed in the desulfurative conjugate addition of alkyl radicals onto Michael acceptors (Scheme 6). Again, the process is based on a photocatalyzed oxidation pathway. The starting sulfonamide (6–1) was first deprotonated by a mild base (K2HPO4), and the resulting anion was easily oxidized to a N-centered radical. Loss of N-sulfinylbenzamide generates the desired radical that gave the adduct 6–3 upon reaction with 6–2 in 75% yield.103 Scheme 6 Desulfurative Strategy for the Conjugate Addition of Alkyl Radicals onto Michael Acceptors In some instances, the radical precursor is a neutral compound. This situation is possible only when the derivative contains a highly oxidizable or reducible moiety. 4-Alkyl-1,4-dihydropyridines (alkyl-DHPs) under PC-free conditions act as radical precursors when combined with photoexcited iminium ion catalysis (Scheme 7). Here, enal 7–1 formed a chiral iminium ion 7–4+ by reaction with amine 7–3. Cation 7–4+ upon visible light excitation oxidized the alkyl-DHP 7–2 that in turn released the radical 7–5• upon fragmentation, along with radical 7–4•. Radical recombination followed by hydrolysis gave the desired alkylated dihydrocinnamaldehyde 7–6 in a satisfactory yield with a good enantiomeric excess (Scheme 7).150 A similar Giese reaction was later proposed, where the alkyl-DHP was excited and a SET reaction with Ni(bpy)32+, acting as an electron mediator, took place. The alkyl radical derived from the radical cation of alkyl-DHP readily attacked a series of Michael acceptors.151 Scheme 7 Alkyl-DHPs as Radical Precursors in Combination with Iminium Catalysis Looking at the other edge of the redox spectrum, easily reducible compounds were devised as radical precursors via a photocatalyzed process. As an example, the incorporation of a N-phthalimidoyl moiety in an organic compound helps its photocatalyzed reduction, ultimately leading to the release of the alkyl radical. A typical case is represented by N-(acyloxy)phthalimides.126 A stereoselective variant of this reaction was applied to the synthesis of (−)-solidagolactone (8–4, Scheme 8). Thus, the photocatalyzed reduction of phthalimide 8–1 by a RuII complex released a tertiary carbon radical. Attack to the terminal carbon of the unsaturated core present in β-vinylbutenolide 8–2 yields 8–3 with a very high diastereomeric excess. Further elaboration of compound 8–3 gave 8–4 in a single step.152 This reaction emerges as a very interesting tool to construct quaternary carbons153 and to synthesize biologically active derivatives, e.g., (−)-aplyviolene.154 Scheme 8 Synthesis of (−)-Solidagolactone via N-(Acyloxy)phthalimides Interesting results were also obtained using N-phthalimidoyl oxalates such as 9–1 in place of the N-(acyloxy)phthalimides for the generation of alkyl radicals starting from tertiary alcohols (Scheme 9).92,97 The similarity of this reaction to the one presented in Scheme 8 is striking, despite a less atom economical radical generation. Scheme 9 Generation of Alkyl Radicals from N-Phthalimidoyl Oxalates Reduction of an organic compound may be carried out even on organic iodides by using cyanoborohydride anion as the reducing agent. The reaction is chemoselective, since no alkyl bromides or chlorides could be activated following this way. Giese adducts were formed by irradiation with a Xe lamp of the reaction mixture in good yields as illustrated by the formation of 10–2 from 10–1 in Scheme 10.155 This is another interesting example to circumvent the use of tin hydrides in the activation of alkyl halides. Scheme 10 Giese-Type Reaction of Iodides in the Presence of BH3CN– Alkyl chlorides can be activated using Ir(dtbby)(ppy)2PF6 in the presence of micelles. The micellar environment stabilizes the photogenerated [Ir(dtbby)•–(ppy)2] species (−1.51 V vs SCE), unable to directly reduce the alkyl chlorides (ca. −2.8 V vs SCE). A second excitation of this long-lived intermediate allows the electron transfer to the halide, which could react with different electron-poor olefins, forging a novel C–C bond. The micellar system allowed intramolecular cyclizations to form five-membered cycles.156 Reduction of the alkyl halide 11–1 could be avoided applying a halogen transfer reaction. In fact, due to the strong BDE of the Si-halogen bond, an alkyl radical is formed thanks to the action of a purposely generated silyl radical (from (Me3Si)3SiH, TTMSS) by a photoredox catalytic step. Radical addition onto an unsaturated amide (11–2) gave the 1,8-difunctionalized derivative 11–3, a key compound in the preparation of Vorinostat 11–4, a histone deacetylase (HDAC) inhibitor active against HIV and cancer (Scheme 11).157 This is the typical case where the radical is formed by the cleavage of an Alk-Br bond without the assistance of tin derivatives. It is interesting that the reaction requires a substoichiometric amount of silane to proceed. Indeed, with higher loadings the product yield decreases, possibly due to the presence of competing nonproductive pathways. A chain reaction mechanism could be envisaged; however, the quantum yield for this reaction (Φ = 0.45) does not fully clarify the mechanistic details of the transformation. Scheme 11 Synthesis of Vorinostat via XAT Strategy In many instances the formation of the alkyl radical arose from a direct or indirect photocatalyzed C–H homolytic cleavage. The excited state of the decatungstate anion in its tetrabutylammonium salt form (TBADT) promoted in several cases the direct chemoselective cleavage of a C–H bond.75,158Scheme 12 depicts two examples involving the hydroalkylation of acrylonitrile. Unsubstituted cycloalkanes were suitable hydrogen donors under flow conditions (yielding 12–1Scheme 12a).159 Moreover, the chemoselective cleavage of the methine hydrogen in isovaleronitrile allowed the preparation of dinitrile 12–2 in 73% yield (Scheme 12b).160 Scheme 12 TBADT-Photocatalyzed Hydroalkylation of Acrylonitrile Similarly, the presence of a tertiary hydrogen was the driving force of the chemoselective TBADT-photocatalyzed C–H cleavage in several derivatives, as depicted in Scheme 13. As an example, alkylpyridine 13–1 was selectively functionalized and gave derivative 13–2 as the exclusive product in the reaction with a vinyl sulfone (Scheme 13a).161 Interestingly, the labile benzylic hydrogens present in 13–1 remained untouched under these reaction conditions. Noteworthy, steric and polar effects cooperatively operated in the derivatization of lactone 13–3. As a result only the methine hydrogen of the isopropyl group was selectively abstracted and afforded 13–4 in very high yields by reaction with fumaronitrile (Scheme 13b), albeit the seven different types of hydrogens present in 13–3.162 The C–H cleavage may also take place in branched alkanes as witnessed by the derivatization of 13–5 to form the succinate derivative 13–6 (Scheme 13c).163 Scheme 13 TBADT-Driven Functionalization of Tertiary Carbons In rare instances, the hydroalkylation reaction may be applied to olefins different to the usual Michael acceptors. Thus, substituted vinylpyridines were functionalized by TBADT-photocatalyzed addition of cycloalkanes. Scheme 14 showed the smooth synthesis of 14–2 starting from 14–1 simply by irradiation of the reaction mixture containing a slight excess of cyclohexane in the presence of a catalytic amount of the decatungstate salt.164 Scheme 14 Functionalization of a Vinylpyridine with a Cycloalkane Recently, alternative PCs have been developed for the direct photocatalyzed activation of C–H bonds in cycloalkanes, namely uranyl cation165 and Eosin Y,166 both having the advantage of absorbing in the visible light region. The alkyl radical formation may be induced by a photogenerated stable radical which acts as a radical mediator. An IrIII based photoredox catalyst oxidized the chloride anion (being the counterion of the Ir complex) to the corresponding chlorine atom, which abstracted a hydrogen atom from cyclopentane, thus forming adduct 15–1 in 69% yield upon addition onto a maleate ester (Scheme 15).167 Scheme 15 Indirect HAT Mediated by a Cl• Radical Another intriguing way to induce the cleavage of unactivated C(sp3)-H bonds is by a photocatalyzed intramolecular hydrogen abstraction. Usually a photoredox or a proton-coupled electron transfer (PCET)47 step induced the formation of a heteroatom centered radical that abstracts a tertiary C–H bond intramolecularly in a selective fashion, following a 1,5-HAT process mimicking the Hoffmann-Löffler-Freytag reaction (Scheme 16).168−170 Scheme 16 Intramolecular 1,5-HAT Forming Tertiary Alkyl Radicals When the reaction was applied to compound 16–1, an oxidative PCET generated a neutral amidine radical that promotes the 1,5-hydrogen atom abstraction forming a tertiary radical which is able to functionalize olefin 16–2 in a complete regioselective fashion affording 16–3 (Scheme 16a).171 The reaction was also applied to medicinally relevant molecules such as the steroid-derived trifluoroacetamide 16–4 (Scheme 16b). Despite the fact that this compound has several labile C–H bonds including tertiary C–H bonds and C–H bonds adjacent to heteroatoms, the intramolecular hydrogen abstraction followed by conjugate addition onto 16–5 gave 16–6 as the sole product.172 The remote activation of the C–H bond in the δ-position following this approach is a general reaction as demonstrated in related systems applied to amides protected with a carbamate group173 or in simple benzamide derivatives.174 In the latter case, the reaction was carried out in the presence of a chiral Rh-based Lewis acid catalyst that allowed the asymmetric alkylation of α,β-unsaturated 2-acyl imidazoles.174 The abstracting species could be likewise a photogenerated iminyl radical as illustrated in Scheme 17. Here a carbonyl group is converted in an oxime derivative (e.g., 17–1) by reaction with an α-aminoxy acid. Photocatalyzed oxidation followed by fragmentation of the resulting carbonyloxy radical gave an iminyl radical prone to a 1,5-HAT to afford a tertiary radical that upon addition to acrylate 17–2 gave compound 17–3 in 77% yield.175 Scheme 17 1,5-HAT Promoted by an Iminyl Radical 2.1.2 Heteroalkylation of C–C Double Bonds An interesting variation of the functionalization of a double bond is the formation of a C–C bond (upon an alkylation step) followed by the formation of another C–Y bond (Y ≠ H) on the adjacent carbon. As an example, alkyl diacyl peroxides were reduced photocatalytically and the fragmentation released an alkyl radical and a carboxylate anion both incorporated in the structure of the product. Thus, 2-vinylnaphthalene 18–2 was converted into compound 18–4 in a very good yield upon reaction with lauroyl peroxide 18–1 upon an oxidative quenching process by consecutive C–C and C–O formation (Scheme 18).176 The reaction was made possible by the oxidation of the resulting radical adduct 18–3• (by RuIII, the oxidized form of the PC) that generated the cation 18–3+ that was easily trapped by the carboxylate anion previously released. Scheme 18 Oxyalkylation via Alkyl Diacyl Peroxides N-(acyloxy)phthalimide 19–1 as radical precursor found use in a similar multicomponent oxyalkylation of styrenes. The addition of the alkyl radical onto the vinylarene followed by the incorporation of water present in the reaction mixture afforded derivative 19–2 in 72% yield (Scheme 19).177 Noteworthy, the labile C–Br bond in 19–1 remained untouched in the process. Scheme 19 Multicomponent Oxyalkylation of Styrenes The use of water as the oxygen source was likewise used in the difunctionalization of aryl alkenes where the carbon-centered radical was formed by an intramolecular 1,5-HAT of a photogenerated iminyl radical.178 Performing the reaction in DMSO, allows for the use of the solvent as an oxygen donor adopting the Kornblum oxidation. The intermediate benzyl radical formed after the alkylation step reacts with the solvent and eventually forming a carbonyl group in place of a simple C–O bond. An elegant example is shown in (Scheme 20) for the synthesis of ketonitrile 20–4.179 A cycloketone oxime ester (20–1) was photocatalytically reduced, inducing a ring opening on the resulting iminyl radical. The resulting cyano-substituted alkyl radical reacted with styrene 20–2, and the addition with DMSO formed the intermediate 20–3, that, upon Me2S loss, afforded the product. Scheme 20 Photocatalyzed Oxyalkylation of Styrenes Based on the Kornblum Oxidation A related oxyalkylation of styrenes made again the use of the Kornblum oxidation as the last step in the synthesis of substituted acetophenones. Indeed, N-hydroxyphthalimides (e.g., 21–1) were employed as the radical source, and an IrIII complex was used as the PC, obtaining good yields even on a 7 mmol scale (64% of 21–3, Scheme 21a).180,181 Ester 21–1 was also adopted for the preparation of the aryl alkyl ketone 21–5 in 61% yield (Scheme 21b). In this case, however, the decarboxylative alkylation was applied to silyl enol ethers having the carbonyl oxygen already incorporated in the initial structure such as 21–4.182 The same process described in Scheme 21b can be carried out under uncatalyzed conditions under blue LED irradiation in the presence of an excess of NaI (150 mol %) and PPh3 (20 mol %). The reaction was based on the photoactivation of a complex formed by N-(acyloxy)phthalimide with NaI and PPh3 through Coulombic and cation-π interactions. In this case, the excitation caused the reduction of the phthalimide by a SET reaction within the complex.183 Scheme 21 Oxyalkylation by Using N-(Acyloxy)phthalimide Derivatives as Radicals Source Alkylated ketones 22–3a–d were likewise obtained by the IrIII-photocatalyzed reaction between a 2-mercaptothiazolinium salt (22–1, as alkyl radical precursor) and silyl enol ethers 22–2a–d (Scheme 22).106 Scheme 22 Synthesis of Alkylated Ketones from Mercaptothiazolinium Salts Lauryl peroxide (LPO, see Scheme 18) was adopted for the Ru-catalyzed three-component carbofluorination of styrenes as illustrated in Scheme 23a. The vinylic double bond of compound 23–1 derived from estrone was functionalized twice by using triethylamine trihydrofluoride Et3N·HF as the fluoride anion source to deliver the desired alkyl-fluorinated olefin 23–2 in 61% yield. The reduction of LPO is mediated by the presence of a copper salt in the role of a cocatalyst in a dual catalytic process.184 The carbofluorination was later applied to dehydroalanine derivative 23–4 by using alkyltrifluoroborates and an excess of Selectfluor as an electrophilic fluorine source (Scheme 23b). The use of a visible light POC ([Acr+Mes]ClO4) allowed for the synthesis of a wide range of unnatural α-fluoro-α-amino acids including F-Leu (23–5).185 Scheme 23 Carbofluorination of (a) Styrenes and (b) Dehidroalanine Derivatives In rare instances, two C–C bonds could be formed in the adjacent position of the double bond as in cyanoalkylations. The enantioselectivity of the reaction was controlled exploiting the capability of a copper catalyst to form complexes with chiral Box ligands. Thus, a methyl radical was obtained by IrIII-photocatalyzed reduction of phthalimide 24–1 that readily attacked styrene (Scheme 24). Meanwhile, the CuI salt incorporated Box 24–2 as the ligand, and the resulting complex reacted with the adduct radical in the presence of TMSCN. As a result, cyanoalkylated 24–3 was obtained in a good yield and in good ee.186 Scheme 24 Enantioselective Cyanoalkylation of Styrenes A particular case of cyanoalkylation was later reported in the photocatalyzed reaction between cyclopropanols and cyanohydrins having a pendant C=C bond. Oxidative ring opening of the three-membered ring followed by addition onto the double bond and cyano migration gave a series of multiply functionalized 1,8-diketones incorporating the cyano group.187 2.1.3 Allylation Allylation reactions can be easily performed by reaction of an alkyl radical with substituted allyl sulfones (mainly with 1,2-bis(phenylsulfonyl)-2-propene 25–1, Scheme 25a). The alkyl radical was generated under visible light irradiation by hydrogen abstraction from cycloalkanes by an aromatic ketone, e.g., 5,7,12,14-pentacenetetrone 25–2. Addition of a cycloalkyl radical onto 25–1 followed by sulfonyl radical elimination gave access to vinyl sulfones 25–3a–b in good yields (Scheme 25a).188 Scheme 25 Allylation through Alkyl Radicals Generated (a) via HAT and (b) from Si bis-Catecholates Other related reactions were designed to forge C(sp3)–allyl bonds following this simple scheme. The alkyl radical was formed by photocatalytic oxidation of hypervalent bis-catecholato silicon compounds as shown in Scheme 25b. Thus, compound 25–4 upon oxidation released the desired substituted alkyl radical, and addition onto allyl sulfone 25–5 gave the corresponding allylated derivative 25–6 in 70% yield.113 Olefin 25–5 was also used in a decarboxylative allylation of alkyl N-acyloxyphthalimides under RuII photocatalysis. The great advantage of the process was the reaction time since the allylation was completed in a few minutes at room temperature.189 A particular class of phthalimides could be employed with no need of a photocatalyst to promote the reaction. N-alkoxyphthalimide (26–1) is able to form a donor–acceptor complex with electron donor compounds, such as the Hantzsch ester HE. Upon excitation, an electron transfer occurred within the complex generating a radical anion, which released an alkoxy radical upon N–O bond cleavage. Loss of formaldehyde formed the desired alkyl radical which reacted with 26–2, to obtain product 26–3 in 60% yield (Scheme 26).127 Scheme 26 Hantzsch Ester Mediated Photocleavage of N-Alkoxyphthalimides Photocatalyzed reduction of Katritzky salts 27–1a–c obtained from the corresponding amines (Scheme 27) gave access to the allylated compounds 27–3a–c. Thus, the monoelectronic reduction of pyridinium salts 27–1a–c caused the release of the corresponding pyridines along with the substituted cyclohexyl radicals than upon trapping by 27–2 efficiently afforded acrylates 27–3a–c.190 Scheme 27 Photocatalyzed Allylation by Using Katritzky Salts A remote allylation under visible light irradiation was devised starting from amide 28–1 making use of eosin Y (EY) as the PC (Scheme 28). The excited EY is able to reduce 28–1 thanks to the electron-withdrawing capability of the substituted phenoxy group on the nitrogen of the amide. The amidyl radical formed upon fragmentation of 28–1•– gave rise to a tertiary radical upon 1,5-HAT, allowing the remote allylation, forming 28–2 in 75% yield.191 Scheme 28 Remote Allylation via Amidyl Radicals A different approach involved the use of trifluoromethyl-substituted alkenes (e.g., 29–1) that upon addition of the alkyl radical gave access to valuable gem-difluoroalkenes such as 29–2a–b (Scheme 29). The oxidation of alkyltrifluoroborates was here assured by the organic photocatalyst 4CzIPN, leading to nonstabilized primary, secondary, and tertiary radicals. The defluorinative alkylation resulted from the reduction of the radical adduct, followed by an E1cB-like fluoride elimination.192 Scheme 29 Synthesis of gem-Difluoroalkenes from Alkyl Trifluoroborates A dual catalytic approach was designed for valuable allylation using vinyl epoxides as allylating agents (Scheme 30). The mechanism was investigated by quantum mechanical calculations [by DFT and DLPNO–CCSD(T)] and supported an initial complexation of Ni0 to 30–2 that quickly underwent a SN2-like ring opening, followed by the incorporation of the alkyl radical formed by DHP-derived compounds 30–1a,b into the metal complex. Allyl alcohols 30–3a,b were then formed by inner sphere C(sp2)-C(sp3) bond formation from the resulting NiIII complex.193 Scheme 30 Dual-Catalytic Allylation of Vinyl Epoxides 2.1.4 sp3–sp3 Cross-coupling Another intriguing possibility offered by the photochemical approach to alkyl radicals is the formation of a C–C bond by a sp3–sp3 cross-coupling reaction. The transformation could lead to novel pathways to interesting targets, as represented by the synthesis of the drug tirofiban in only four steps, starting from easily available compounds. The protocol made use of two consecutive photocatalyzed reactions applying a metallaphotoredox strategy (Scheme 31). The key step is the coupling between carboxylic acid 31–1 and alkyl halide 31–2. The halide is first complexed by a Ni0 catalyst and the resulting NiI complex trapped the alkyl radical (obtained by photocatalyzed decarboxylation) to yield a NiIII complex that in turn released the sp3–sp3 coupled product 31–3 after desilylation with TBAF. The desired tirofiban was then obtained by elaboration of 31–3 in two subsequent steps.194 Scheme 31 Synthesis of a Precursor of Tirofiban by a Metallaphotoredox Strategy Another example of a C(sp3)–C(sp3) cross-coupling process is the reaction between alkylsilicates and alkyl halides. As in the previous case, a dual catalytic Ir/Ni system was required.195 The alkyl radical may be likewise generated from an alkyl halide by a halogen atom transfer with a photogenerated silyl radical (from a silanol). The radical that is hence formed could be coupled with another alkyl bromide, e.g., methyl bromide, using a Ni0 catalyst to perform valuable methylation reactions.196 Aliphatic carboxylic acids were used to form alkyl-CF3 bonds via a photocatalyzed reaction making use of Togni's reagent as the trifluoromethylating agent. The reaction was promoted under visible light irradiation employing an IrIII photocatalyst coupled with a CuI salt. This process tolerates various functionalities including olefins, alcohols, heterocycles, and even strained ring systems.197 The alkylation of a benzylic position in N-aryl tetrahydroisoquinoline 32–1 was reported following two different approaches (Scheme 32). The first allowed the reaction of an unactivated alkyl bromide (32–2) by the excitation of a Pd0 complex. Compound 32–1 was oxidized in the catalytic cycle, and the resulting α-amino radical coupled with the isopropyl radical to form 32–4 in 81% yield (Scheme 32a).198 An alternative heavy-metal-free route catalyzed by a dye-sensitized semiconductor is depicted in Scheme 32b. Excitation of an inexpensive dye (erythrosine B) caused the reduction of titanium dioxide that in turn was able to reduce phthalimide 32–3 that eventually yielded quinoline 32–4.199 Scheme 32 Different Strategies in the Alkylation of N-Aryl Tetrahydroisoquinolines 2.1.5 Other Reactions In particular cases, a C=N bond can be made sufficiently electrophilic to undergo alkyl radical addition as in the case of N-sulfinimines, exploited for the preparation of protected amines. A high degree of diastereoselectivity can be obtained when starting from chiral N-sulfinimines (33–2a–c, Scheme 33). Thus, the asymmetric addition of an isopropyl radical (formed from derivative 33–1) onto 33–2a–c allowed the isolation of sulfinamides 33–3a–c in good yields.200 Scheme 33 Addition of an Alkyl Radical to Chiral Sulfinimines The alkylation of related imines can be carried out by using ammonium alkyl bis(catecholato)silicates as the radical precursors under metal-free conditions adopting 4CzIPN as the POC201 or by using potassium alkyltrifluoroborates in the alkylation of N-phenylimines.202 Another particular case is the alkylative semipinacol rearrangement devised for the synthesis of 2-alkyl-substituted cycloalkanones. The reaction involved the photocatalytic reaction between TMS protected α-styrenyl substituted cyclic alcohol 34–2 and the unactivated bromoalkane 34–1 (Scheme 34a). The reaction was promoted by the dimeric gold complex [Au2(dppm)2]Cl2. This complex is able to reduce 34–1 (ca. −2.5 V vs SCE) despite having an oxidation potential in the excited state considerably lower for the reaction to occur (ca. −1.63 V vs SCE). This can be explained by the formation an inner sphere exciplex between the excited dimeric catalyst and 34–1 that promotes the otherwise thermodynamically unfeasible redox process, generating an AuI–AuII dimer and 34–4•. The combination of the latter species formed an AuIII complex that induces a semipinacol rearrangement coupled with C(sp3)–C(sp3) reductive elimination, which furnished 34–3 in 84% yield (Scheme 34b).203 Scheme 34 Gold Catalyzed Activation of Bromoalkanes A similar reaction was later developed starting from cycloalkanol-substituted styrenes and N-acyloxyphthalimides under IrIII photocatalysis.204 2.2 Formation of a C(sp3)-C(sp2) Bond 2.2.1 Alkenylation The reaction between an alkyl radical with a cinnamic acid followed by loss of the COOH group is one of the more common approaches to promote an alkenylation reaction. Thus, the radical formed from salt 35–3 attacked the benziodoxole adduct 35–2, synthesized from acrylic acid 35–1. The reaction yielded 83% of the diphenylethylene derivative 35–4 upon a deboronation/decarboxylation sequence (Scheme 35).205 The benziodoxole moiety gave efficient results in promoting the radical elimination step, while other noncyclic IIII reagents were ineffective. Scheme 35 Alkenylations Mediated by Benziodoxole Different decarboxylative alkenylations have been reported by changing the radical source and the photocatalyst (Scheme 36). The homolytic cleavage of an alkyl-I bond has been promoted by a CuI complex and the resulting cyclohexyl radical afforded styrene 36–3 in 68% yield upon addition onto cinnamic acid 36–1 (path a).206 The same product may be formed as well starting from the same substrate by using phthalimide 36–2 under visible light irradiation with the help of an IrIII207 (path b) or a RuII photocatalyst.208 As an additional bonus, the formation of adduct 36–3 was obtained with a preferred E configuration. Scheme 36 Different Strategies Toward Decarboxylative Alkenylations The alkenylation may mimic a Heck reaction as in the visible light-induced Pd-catalyzed reaction between a vinyl (hetero)arene and an α-heteroatom-substituted alkyl iodide or bromide (see Scheme 37). Here, the generation of the radical is induced by the reduction of the TMS-derivative 37–1 by the excited Pd0 species. Radical addition onto 37–2 followed by β-H-elimination from the adduct radical delivered allyl silane 37–3 in 81% yield.209 Noteworthy, the same reaction did not take place under usual thermal Pd-catalysis. Scheme 37 Heck-Like Alkenylation of an Alkyl Iodide Alkylation of styrenes could be carried out using an inexpensive palladium source (Pd(PPh3)4) with no need of any base or classical photocatalyst. The reaction was promoted by visible light, adopting N-hydroxyphthalimides as radical sources.210 Other visible light Pd promoted alkenylations include the reaction of vinyl arenes with carboxylic acids211 or tertiary alkyl halides212 as radical precursors. Other metal catalysts, however, were helpful for the substitution of a vinylic hydrogen atom with an alkyl group. In this respect, a dinuclear gold complex was employed for the activation of an alkyl bromide to promote a photocatalyzed Heck-like reaction.213 The synergistic combination of a POC and a cobaloxime catalyst promoted the photocatalyzed decarboxylative coupling between 38–1 and styrene 38–2 to give the alkenylated product 38–3 in 82% yield and with a complete E/Z selectivity as illustrated in Scheme 38.214 Scheme 38 Cobaloxime-Mediated Decarboxylative Coupling of Carboxylic Acids with Styrenes The addition of the alkyl radical may take place even on substituted alkenes via an ipso-substitution reaction. An example is shown in Scheme 39 where a vinyl iodide (39–2) is used for an alkenylation by the reaction with a radical generated from silicate 39–1, obtaining compound 39–3. The RuII photocatalyst in the dual catalytic system has the role of generating the radical, while the Ni0 catalyst activates the C(sp2)-I bond.215 Scheme 39 Alkenylation via Alkenyl Iodides Alkenylation of alkyl iodide 40–1 can also take place starting from an alkenyl sulfone (40–2). Also in this case, an ipso-substitution is central to the novel bond formation and the Pd0 catalyst formed the radical by a SET reaction with 40–1. After the addition of the radical onto 40–2, the sequence is completed by the elimination of a sulfonyl radical affording 53% yield of 40–3 (Scheme 40).216 Scheme 40 Alkenylation of an Alkyl Iodide with Alkenyl Sulfones Alkyl bromides were used in alkenylations by reaction with vinyl sulfones made possible by the photocatalytic generation of silicon centered radical that in turn formed the alkyl radical by a halogen atom transfer reaction.217 2.2.2 Acylation Acylation owes its importance to the possibility to convert an alkyl radical into a ketone, a reaction that proceeds in most cases with the intermediacy of an acyl radical.218,219 A classical approach is based on the homolytic cleavage of an alkyl-I bond followed by carbonylation with CO and reaction with electrophiles of the resulting nucleophilic acyl radical. Scheme 41 illustrates the concept. Irradiation of iodide 41–1 with a Xe lamp in the presence of CO (45 atm) and a Pd0 complex led to an electron transfer reaction which formed an alkyl radical that, upon carbonylation and addition onto phenyl acetylene, gave ynone 41–2 in 63% yield.220 The reaction is supposed to proceed via a photoinduced electron transfer from the Pd0 catalyst to the iodoalkane, furnishing a PdII species and the alkyl radical. The carbon-centered radical promptly reacts with CO to generate an acyl radical. The PdI catalyst intervenes here again to couple the acyl derivative with the alkyne, preserving the triple bond in the final product. This reaction was later applied to the acylation of styrenes to give the corresponding enones.221 The electrophilic nature of the alkyne could be exploited if the moiety is placed in the same reagent bearing the iodide. In this case, the first reaction observed was an intramolecular cyclization forming an alkenyl radical which eventually reacted with CO, furnishing an α,β-unsaturated ketone.222 Scheme 41 Photocatalyzed Synthesis of Ynones A reductive step induced the generation of the alkyl radical through an IrIII-photocatalyzed C–N bond activation in pyridinium salt 42–1 (Scheme 42). Trapping of the alkyl radical with CO followed by addition onto 1,1-diphenylethylene gave access to the Heck-type product 42–2 with no interference by the 2,4-dioxo-3,4-dihydropyrimidin-1-yl ring.223 Scheme 42 Synthesis of Enones via Photocatalyzed C–N Bond Activation The alkyl radical to be carbonylated was likewise formed starting from a cycloalkane for the preparation of unsymmetrical ketones via radical addition onto Michael acceptors. The reaction proceeded via a photocatalyzed decatungstate hydrogen atom transfer reaction224 When cyclopentanones were subjected to the photocatalyzed C–H activation, a regioselective β-functionalization occurred. Thus, 1,4-diketones 43–3a–c were smoothly formed by reaction of the photogenerated acyl radical 43–1• onto Michael acceptors 43–2a–c (Scheme 43).225 Scheme 43 Photocatalyzed Synthesis of Unsymmetrical Ketones Unsymmetrical ketones have been likewise formed by carbonylation of alkyl radicals generated from organosilicates by using 4CzIPN as POC under visible-light irradiation.226 Potassium alkyltrifluoroborates were extensively used for acylation reactions having recourse to a dual photocatalytic system. The unstabilized alkyl radical was generated from trifluoroborate 44–1 with the help of an IrIII PC (Scheme 44). Meanwhile, the acid 44–2 was converted in situ into a mixed anhydride (by reaction with dimethyl dicarbonate, DMDC) that was activated by a Ni0 complex. Addition of the alkyl radical onto the resulting complex led to the acylated product 44–3.227 In a similar vein, Ir-photoredox/nickel catalytic cross-coupling reactions were devised by using acyl chlorides228 and N-acylpyrrolidine-2,5-diones229 as acylating reagents. Scheme 44 Dual Catalytic Acylation of Alkyl Trifluoroborates A Ni/Ru, dual-catalyzed amidation protocol was possible thanks to the coupling between an alkylsilicate and an isocyanate. Even in the latter case, the alkyl radical attacked the complex formed between the isocyanate and a Ni0 species and, as a result, the mild formation of substituted amides took place.230 The acylation of the radical was also exploited for the synthesis of esters. This elegant approach involves the generation of radicals from unactivated C(sp3)–H bonds (e.g., in cycloalkanes). The hydrogen abstraction on cycloalkanes was induced by a chlorine atom released from the photocleavage of the complex formed between chloroformate 45–1 and a Ni0 complex, allowing one to synthesize scaffolds with different ring sizes (45–2a–d in Scheme 45).231 Scheme 45 Dual Catalytic Acylation of Cycloalkanes 2.2.3 Minisci-Like Reactions A fundamental transformation for the construction of C(sp2)-C(sp3) bond is the Minisci reaction, where the functionalization of heteroaromatics took place by substituting a H atom with an alkyl group. The reaction was widely investigated in the last years and mainly involves the functionalization of a nitrogen-containing heterocycle.232 An interesting example is the methylation reported in Scheme 46.94 A methyl radical was formed by using a peracetate such as 46–1. The protonation of 46–1 by acetic acid facilitates a PCET reduction of the peracetate by the IrIII PC. A double fragmentation ensued, and the resulting methyl radical may attack the protonated form of biologically active heterocycles (e.g., fasudil 46–2) in a mild selective manner to afford 46–3 in 43% yield.94 Scheme 46 Alkylation of Fasudil Another approach made use of an alkyl boronic acid as the radical precursor. The process is initiated by the RuII-photocatalyzed reduction of acetoxybenziodoxole (BI-OAc) that liberated the key species ArCOO• (Scheme 47). Upon addition onto an alkyl boronic acid, this ortho-iodobenzoyloxy radical made available the alkyl radical that in turn functionalized pyridine 47–1 in position 2 in 52% yield (47–2, Scheme 47).233 Scheme 47 Minisci Reaction by Using Alkyl Boronic Acids The generation of the alkyl radical from boron-containing derivatives was made easier starting from alkyltrifluoroborates. A POC (Acr+Mes) is, however, required, but in all cases, the regioselective functionalization of various nitrogen-containing heterocycles was achieved.234 A related chemical oxidant-free approach process was later developed where alkyl radicals were formed by merging electro and photoredox catalysis.235 Alkyl halides are versatile substrates for the photoinduced functionalization (e.g., butylation) of lepidine 48–1 (Scheme 48). An uncatalyzed redox process is a rare occurrence here, since alkyl halides reduction is more demanding. This drawback can be overcome by the adoption of a dimeric AuI complex (see Scheme 34) that upon excitation coordinates an unactivated haloalkane promoting an inner sphere PET. This interaction pushes the activation of R-Br despite its larger Ered with respect to the PC (Scheme 48a).236 A different approach promoting the homolytic cleavage of the R-I bond is shown in Scheme 48b. Decacarbonyldimanganese Mn2(CO)10 was cleaved upon visible light irradiation, and the resulting Mn-based radical was able to abstract the iodine atom from an alkyl iodide thus generating the desired butyl radical. This route was smoothly applied to the late-stage functionalization of complex nitrogen-containing substrates.237 Moreover, the activation of alkyl halides may be obtained by the photogeneration of a silyl based radical derived by TTMSS (Scheme 48c, see also Scheme 11). The robustness and the mildness of this approach was witnessed by the broad substrate scope and the compatibility of several functional groups present in the radical.238 The use of acidic conditions (required to make the nitrogen heterocycle more electrophilic) may however be avoided. Excited [Ir(ppy)2(dtbbpy)]PF6 was sufficiently reducing to convert alkyl iodides to alkyl radicals under basic conditions by combining conjugate and halogen ortho-directing effects.239 Scheme 48 Photocatalyzed Butylation of Lepidine In general, lepidine is the preferred substrate to test new ways for the C–H alkylation of heteroarenes. Accordingly, adamantane carboxylic acid 49–1 served for the visible light induced synthesis of 49–3 starting from lepidine 49–2 (Scheme 49). An IrIII PC was adopted to alkylate various nitrogen heterocycles, making use of a large excess of persulfate anion as the terminal oxidant (path a).240 The presence of a PC is not mandatory for the adamantylation reaction with (bis(trifluoroacetoxy)-iodo)benzene as starting material. This compound in the presence of a carboxylic acid gave the corresponding hypervalent iodineIII reagent that upon irradiation generates the alkyl radical. The TFA liberated in the process was crucial for the activation of the nitrogen heterocycle and adduct 49–3 was
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