The area of catalysis of radical reactions has recently flourished. Various reaction conditions have been discovered and explained in terms of catalytic cycles. These cycles rarely stand alone as unique paths from substrates to products. Instead, most radical reactions have innate chains which form products without any catalyst. How do we know if a species added in "catalytic amounts" is a catalyst, an initiator, or something else? Herein we critically address both catalyst-free and catalytic radical reactions through the lens of radical chemistry. Basic principles of kinetics and thermodynamics are used to address problems of initiation, propagation, and inhibition of radical chains. The catalysis of radical reactions differs from other areas of catalysis. Whereas efficient innate chain reactions are difficult to catalyze because individual steps are fast, both inefficient chain processes and non-chain processes afford diverse opportunities for catalysis, as illustrated with selected examples.

Catalysis of Radical Reactions: A Radical Chemistry Perspective.

Carbon trifluoromethylation reactions of hydrocarbon derivatives and heteroarenes.

Alkylation reactions represent an important organic transformation to form C–C bonds. In addition to conventional approaches with alkyl halides or sulfonates as alkylating agents, the use of unactivated olefins for alkylations has become attractive from both cost and sustainability viewpoints. This Review summarizes transition-metal-catalyzed alkylations of various carbon–hydrogen bonds (addition of C–H bonds across olefins) using regular olefins or 1,3-dienes up to May 2016. According to the mode of activation, the Review is divided into two sections: alkylation via C–H activation and alkylation via olefin activation.

Transition-Metal-Catalyzed C–H Alkylation Using Alkenes

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Chemicals from Alkynes with Palladium Catalysts

s a hydrogen atom from the thiol to give hydroperoxide 96 and a thiyl radical, which propagates the chain. Hydroperoxide 96 is reduced in the presence of triphenyl phosphine to give the corresponding alcohol 91. The preference for the formation of cis-3,5-disubstituted 1,2-dioxolanes is in agreement with the Beckwith−Houk transition state model for 5-exo-trig cyclizations. Similarly, the addition of thiophenol onto 5methylhepta-1,3,6-triene 97 under an atmosphere of oxygen led to 1,2-dioxolane 98, isolated in 49% as a single diastereoisomer after treatment with triphenyl phosphine, together with minor amounts of linear alcohols 99 and 100 (Scheme 49, eq b). This reaction is remarkable for a number of reasons. First, the addition of the thiyl radical occurs exclusively at the terminal position of the conjugated diene system and not at the terminal alkene, thus highlighting the higher reactivity of conjugated dienes as compared to isolated alkenes. Second, intermolecular trapping of the resulting allyl radical is reversible and regioselective under these reaction conditions. Because of the reversibility of the reaction between the allyl radical and molecular oxygen, both ratios 1,4/1,2-addition and 1,2dioxolane/linear alcohols strongly depend upon the initial concentration in thiol. Accordingly, the 1,2-dioxolanes were obtained in good yields only in highly diluted solutions. Finally, the 5-exo-trig cyclization occurs in a completely stereoselective manner, with only one of the two diastereomeric peroxyl radical intermediates (101) undergoing cyclization, while the other one (102) either leads to linear alcohol 99 or fragments back the allyl radical (Scheme 49, eq b). The reversible reaction of allyl radicals with molecular oxygen was also demonstrated for carotenoid-derived carbon-centered radical generated by Scheme 47 Scheme 48. Application to the Preparation of Functionalized 1,2,4-Trioxanes Chemical Reviews Review dx.doi.org/10.1021/cr400441m | Chem. Rev. XXXX, XXX, XXX−XXX X addition of a thiyl radical to the conjugated polyene carotene. This process has been extended to include the more challenging 1,5-dienes, from which six-membered ring endoperoxides can be obtained. Bachi and co-workers applied the thiol−olefin cooxidation process to the total synthesis of antimalarial agent yingzhaosu A (Scheme 50) and its C14epimer, as well as the preparation of a series of active analogues, from readily available limonene 103. The overall process is extremely challenging in this case due to the particular structure of the diene, with the 6-exo-cyclization process being in competition with intermolecular hydrogen atom abstraction from the thiol, and also potentially with intramolecular hydrogen abstraction from the activated allylic position by the reactive oxygen-centered radical. As previously observed, addition of the thiyl radical takes place at the less hindered position, and due to the lack of stereocontrol during the trapping of the resulting carbon-centered radical, peroxyl radical 105 is formed as a 1:1 mixture of diastereoisomers (Scheme 50). The latter undergoes 6-exo-trig cyclization to give carbon-centered radical 106. Unlike the initial trapping with molecular oxygen, the 2,3-dioxabicyclo[3.3.1]nonane system of 106 allows a highly diastereoselective reaction for the second trapping with molecular oxygen from the less hindered face to give 107. Alcohol 104 is then obtained following hydrogen abstraction from the thiol by peroxyl radical 107 and reduction of the resulting hydroperoxide with triphenylphosphine. The yields of endoperoxides remain relatively low (ca. 20−30%, calculated on the diene); however, considering the accessibility and the cost of the reactants (thiophenol, limonene, and oxygen), this approach represents a very attractive access to these structurally complex endoperoxides, some of which exhibit very promising activity for the treatment of malaria. 3.3.2. Intramolecular Trapping of the Carbon-Centered Radical. 3.3.2.a. Fragmentation Reaction: RingOpening of Vinyl Cyclopropanes. The carbon-centered radicals generated by addition of a thiyl radical onto the C C bond of vinylcypropanes have been shown to undergo cyclopropane ring-opening. The resulting radical species can then be trapped by hydrogen abstraction from the thiol. This fragmentation is a very fast process with rate constants in the range 10−10 s−1 (310 K) for most of the cyclopropylcarbinyl radicals, which allows for the fragmentation process to compete favorably with intermolecular reactions, as well as with most intramolecular processes. Alternatively, the carboncentered radical resulting from the β-fragmentation of the cyclopropylmethyl radical can engage further in carbon−carbon bond-forming processes. The allylsulfide moiety allows for the addition of radicals with concomitant release of a thiyl radical, and very elegant processes using only substoichiometric amounts of a source of thiyl radicals have been developed for the rearrangement of vinylcyclopropanes (see section 5.2.1.e). In particular, under nonreducing conditions and in the presence of an external olefin, efficient annulation reactions have been achieved, giving access to polycyclic compounds. The carboncentered radicals generated by the thiol-mediated ring-opening Scheme 49 Scheme 50 Chemical Reviews Review dx.doi.org/10.1021/cr400441m | Chem. Rev. XXXX, XXX, XXX−XXX Y of vinylcyclopropanes could also be trapped to form a new carbon−heteroatom bond. Here again, annulations taking advantage of the allylsulfide moiety have been developed (see section 5.2.1.e). Landais, Renaud, and co-workers used vinyl cyclopentenes such as 108, easily prepared by monocyclopropanation of silylcyclopentadienes, as radical acceptors for photogenerated thiyl radicals. The reversible addition of the thiyl radical onto the CC bond of 108 leads eventually to cyclopropylcarbinyl radical 110, which undergoes fragmentation to give carboncentered radical 111, stabilized by the neighboring ester group. Hydrogen atom abstraction from the thiol then furnishes cyclopentene 109 and regenerates a thiyl radical that propagates the chain (Scheme 51, eq a). The addition of the thiyl radical at the β-carbon center takes place in a highly stereoselective manner, opposite to the bulky silyl group. The fate of the stabilized carbon-centered radical resulting from the fragmentation process depends upon the reaction conditions. For instance, Naito and co-workers reported the use of vinylcylopropyl oxime ethers such as 112 in domino reactions promoted by a thiol or a disulfide in the presence of triethylborane. The ring-opening of the cyclopropyl moiety is initiated by addition of a thiyl radical onto the terminal position of vinylcyclopropyl oxime ether 112. The stabilized carboncentered radical resulting from the fragmentation process reacts with triethylborane to form a boryl enamine 115 (Scheme 51, eq b). Depending on the reaction conditions, the latter can engage further in a radical oxygenation process, leading eventually to α-hydroxy oxime ether 113 after reduction of peroxyl radical 116 by the thiol (Scheme 51, eq b). Alternatively, 113 can react with aldehydes in an ionic aldol process to give β-hydroxy oxime ethers in a stereoselective manner, as illustrated by the preparation of 117 from 112 (Scheme 51, eq c). In the aforementioned reactions, the allylsulfide moieties generated upon addition of a thiyl radical onto the vinylcyclopropane unit remain intact at the end of the reaction. However, radical reactions taking advantage of the fragmentation of allyl sulfides upon addition of radical species are also well documented. Some examples of intermolecular additions, as well as cyclization and annulation processes, will be described in section 5.2.1.e. 3.3.2.b. Rearrangement and Cyclization of Nonconjugated Dienes. In the addition of thiyl radicals onto nonconjugated dienes, the CC bonds can either react independently or lead to rearrangements through intramolecular trapping of the carbon-centered radical generated in the initial addition step. In many cyclic dienes, addition occurs selectively at the more strained double bond, and products resulting from rearrangements are often observed. For example, the addition of thiophenol to 5-methylene-norbornene led to the exo addition products 118 and 119, together with tricyclic adduct 120. The latter results from the rearrangement of homoallyl radical intermediate 121 into cyclopropylcarbinyl radical 122 (Scheme 52). Similar rearrangements have been observed in norbornadiene derivatives where substitution at C-7 can influence facial selectivity, while substitution of the methylene bridge in 7,7-dimethylnorbornene proved to have no effect in directing the addition of thiophenol. The formation of cyclopropylcarbinyl radical intermediates in norbornadiene derivatives can also lead to other skeletal rearrangements, as illustrated by the addition of thiophenol to hexachloronorbornadiene 123, which results in the formation of 125, beside the expected 1:1 addition product 124 (Scheme 53, eq a). Following addition of the thiyl radical, presumably from the less hindered endo-face, and subsequent 3-exo-trig cyclization onto the neighboring CC bond, cyclopropylcarbinyl radical 126 undergoes fragmentation to give the more stable α-chlorosubScheme 51 Scheme 52 Chemical Reviews Review dx.doi.org/10.1021/cr400441m | Chem. Rev. XXXX, XXX, XXX−XXX Z stituted carbon-centered radical 127. The latter then abstracts a hydrogen atom from the thiol to give 125 (relative configuration not established) and a thiyl radical, which goes on to propagate the chain. Similar rearrangement was observed i n t h e add i t i on o f t BuSH on to 1 , 2 , 3 , 4 , 7 , 7 hexamethylbicyclo[2.2.1]heptadiene. Likewise, Hodgson and co-workers have observed complete skeletal rearrangements in the addition of thiophenol to 7-azabicyclo[2.2.1]heptadienes such as 128 (Scheme 53, eq b). Transa

Thiyl Radicals in Organic Synthesis

Five-membered ring systems are ubiquitous throughout natural products and synthetic therapeutics, and thus, efficient methods to access this essential scaffold are required. Herein, we report the thioacid-mediated, 5-exo-trig cyclization of various 1,6-dienes, with high yields of up to 98%. The labile thioester functionality can be exploited to generate a free thiol residue which can be used as a functional handle or removed entirely to provide the traceless cyclized product.

https://pubs.acs.org/doi/pdf/10.1021/acs.joc.3c00824

Traceless Thioacid-Mediated Radical Cyclization of 1,6-Dienes.

A four-step one-pot procedure involving generation of α-bromo aluminum acetals, their subsequent radical cyclization followed by oxidation of the resulting cyclic aluminum acetals and base promoted double bond migration is developed to convert α-bromoesters derived from propargylic alcohols to butenolides.

Synthesis of Polysubstituted γ‐Butenolides via a Radical Pathway: Cyclization of α‐Bromo Aluminium Acetals and Comparison with the Cyclization of α‐Bromoesters at High Temperature.

Abstract. The direct hydroperfluoroalkylation of a wide range of unactivated alkenes have been achieved at room temperature with readily available iodoperfluoroalkanes using 4-tert-butylcatechol as a source of hydrogen atom and triethylborane. The hydrotrifluoromethylation could also be achieved under these conditions using gaseous trifluoromethyl iodide. An experimentally simple two-step, one-pot hydrotrifluoromethylation process using the easy-to-use trifluoromethanesulfonyl chloride as the source of trifluoromethyl radicals has also been developed. Using these two approaches, a broad range of substrates, including isoprenoid natural products, were efficiently derivatized. 

Fabrice Dénès

Papers

Traceless Thioacid-Mediated Radical Cyclization of 1,6-Dienes.

Synthesis of Polysubstituted γ‐Butenolides via a Radical Pathway: Cyclization of α‐Bromo Aluminium Acetals and Comparison with the Cyclization of α‐Bromoesters at High Temperature.

Radical Mediated Hydroperfluoroalkylation of Unactivated Alkenes