Radical Cyclization-Initiated Difunctionalization Reactions of Alkenes and Alkynes

Abstract

Radical reactions are powerful in the synthesis of diverse molecular scaffolds bearing functional groups. In previous review articles, we have presented 1,2-difunctionalizations, remote 1,3-, 1,4-, 1,5-, 1,6- and 1,7-difunctionalizations, and addition followed by cyclization reactions. Presented in this paper is radical cyclization followed by the second functionalization reaction. The second functionalization could be realized by atom transfer reactions, radical or transition metal-assisted coupling reactions, and reactions with neutral molecules, cationic and anionic species.

1. Introduction

Feasible radical transformations including addition, cyclization, coupling, atom or group transfer, rearrangement, and fragmentation reactions have made radical reactions a powerful tool for making carbon-carbon and carbon-heteroatom bonds [1,2]. The recent developments in radical cyclative functionalization [3,4], radical-enabled bicyclization [5], photoredox reactions [6,7,8], mechanoredox reactions [9], electrochemical reactions [10], and transition metal-assisted radical reactions [11,12,13,14] have empowered the utility of synthetic radicals. Radical reactions being performed in a cascade sequence for the assembling of complex molecular scaffolds with multiple functional groups in regio- and diastereoselective manners is a unique feature. In addition to the cascade reaction sequence, the final radical intermediates could be trapped by radicals or other active species to introduce new functional groups. This process makes the radical reactions even more attractive.

Radical difunctionalization is an attractive topic due to its advantages of synthetic efficiency and product structure diversity. There are a number of reviews on this topic [15,16,17,18,19,20,21,22,23,24,25]. In our recent review articles, we highlighted 1,2-difunctionalization of alkenes and alkynes (Scheme 1, I) [26], remote 1,3-, 1,4-, 1,5-, 1,6- and 1,7-difunctionalization of alkenes and alkynes (Scheme 1, II) [27], and addition/cyclization sequence of dienes, enynes and related compounds (Scheme 1, III) [28]. Presented in this paper are radical cyclization-initiated reactions followed by the second functionalization for the synthesis of cyclic compounds (Scheme 1, IV). It covers the work of the past decade, but most are from the last five years. The second functionalization reaction could be accomplished by atom transfer reactions, radical or transition metal coupling reactions, and reactions involving neutral molecules, cationic and anionic species (Scheme 2). In the reaction process, radical cyclization is considered the first functionalization, while the introduction of X or Y groups is the second functionalization.

It is noteworthy that the reactions covered in this paper involve only a single cyclization. More sophisticated double or multiple cyclization reactions are not included in this paper.

2. Second Functionalization with X via Atom-Transfer Radical Cyclization

In atom-transfer radical cyclization (ATRC) reactions, radicals I-A generated from the homolytic cleavage of X–C bond undergo cyclization to form radicals II-A followed by coupling with radical X for the second functionalization to give products (Scheme 3). A majority of radical cyclization-initiated difunctionalization are ATRC reactions. The common X groups could be I, Br and Cl atoms, or carbonate, pyridinyl, xanthyl, and (2,2,6,6-tetramethylpiperidin-1-yl)-oxyl (TEMPO)-related groups. The reactions presented in this section are classified based on the substrates which include halo-alkenes or -alkynes, N-allyl-haloacetamides, N-allyl-haloamines, O-allyl-halo ethers, O-allyl-halo- hemiacetal acetates and other related compounds.

2.1. Halo Alkenes or Alkynes as Substrates

The iodine atom is a good transfer group for ATRC. In 2017, Martin and coworkers developed a visible light-promoted ATRC reaction of unactivated alkyl iodides for the synthesis of (iodomethylene)cyclopentanes. The reaction was carried out using alkyl iodides 1 in the presence of [Ir(ppy)₂(dtbbpy)]PF₆ and i-Pr₂NEt in t-BuCN under blue LEDs irradiation at room temperature for 12 h to give products (iodomethylene)cyclopentanes 2 in good to excellent yields (Scheme 4) [29]. The suggested reaction mechanism indicates that radicals 3 generated via a single electron transfer (SET) process of alkyl iodides 1 with [Ir^II] undergo a 5-exo cyclization to give radicals 4 and then lead to the formation of products 2 after trapping the iodine radical from alkyl iodides 1.

In 2019, Zhang and coworkers reported a visible-light-induced ATRC reaction of alkyl iodides for the synthesis of cyclic alkenyl iodides (Scheme 5) [30]. The Mn₂(CO)₁₀-catalyzed reaction of alkyl iodides 5 under the irradiation of blue LEDs in cyclohexane at room temperature gave products 6 in moderate to excellent yields. The reactions of natural products such as (−)-borneol and L-menthol also afforded the corresponding products in excellent yields. The proposed reaction mechanism suggested that the Mn(CO)₅ radical is generated by the photo-induced Mn−Mn bond homolysis of Mn₂(CO)₁₀. The reaction of alkyl iodides 5 with the Mn(CO)₅ radical affords radicals 7 which undergo 5-exo cyclization to form radicals 8 followed by iodine atom transfer from 5 to give products 6.

Other than iodoalkyl group, iodoaryl groups are also good for ATRC. Guo and coworkers, in 2019, introduced a photo-induced ATRC reaction of aryl iodide for the synthesis of iodine-substituted fluorene derivatives. The reaction of aryl iodide 9 with photosensitizer thioxanthone (Q₁) under the irradiation of purple LEDs in CH₂Cl₂ at room temperature gave products 10 in good to excellent yields (Scheme 6) [31]. The reaction process involves the formation of triplet 9 via SET reduction in the photoexcited state [Q₁]^* species to [Q₁]^•+. The Ar–I bond cleavage of triplet 9 produces aryl radicals 11 and the iodine radical. Subsequential radical cyclization to form 12 followed by the iodine radical coupling affords products 10.

2.2. N-Allyl-haloacetamides as Substrates

N-Allyl-haloacetamides have been used as the substrates for ATRC to make N-containing heterocyclic compounds. A BEt₃/O₂-initiated iodine-atom-transfer radical cyclization of N-(but-3-en-1-yl)-N-(tert-butyl)-2-iodoalkanamides for the synthesis of iodine substituted δ-lactams has been reported by Li, Liu and their coworkers in 2016. The reaction of N-(but-3-en-1-yl)-N-(tert-butyl)-2-iodoalkanamides 13 in the presence of BEt₃ and air for 1 h afforded products 14 in good yields (Scheme 7) [32]. In this reaction process, radicals 15 formed via the abstraction of iodine atom of 13 by BEt₃ undergo the 6-exo cyclization to give radicals 16 followed by coupling with iodine radical to form products 14.

In 2020, Bolm and co-workers reported a mechanochemical reaction of N-allyl- 2-bromo-propanamides for the synthesis of brominated lactams. The reaction of N-allyl-2-bromo-propanamides 17 in the presence of the mineral covellite and tris[2-(dimethyl-amino)ethyl]amine (Me₆TREN) under mechanochemical conditions in ball mills gave 18 in good to excellent yields (Scheme 8) [33]. The reaction of N-allyl-2-bromo-propanamides 17 and [Cu^IL] generated from covellite and Me₆TREN afford radicals 19 which undergo 5-exo cyclization to give radicals 20 followed by bromide atom transfer from [Cu^IIL]Br to close the catalytic cycle and form products 18. In another paper, Bolm and co-workers conducted similar reactions but modified the reaction conditions by using Cu(OTf)₂, tris(2-pyridylmethyl)amine (TPMA) and tet-BaTiO₃ to give brominated lactams in good yields [34].

In 2021, Yang and coworkers developed cytochromes P450 metalloenzyme-catalyzed radical cyclization reactions of bromo-propanamides for the synthesis of nitrogen heterocycles. The reaction of 2-bromo-propanamides 21 in the presence of whole-cell biotransformation E. coli cells resuspended in M9-N buffer (pH 7.4) at room temperature gave products 22 in good yields (Scheme 9) [35]. γ-Lactam product 22a was obtained in a good diastereomeric ratio of 24:1 which is better than the traditional Cu(OTf)₂/TPMA catalysis of 64:36 diastereomeric ratio [34]. In this metalloenzymatic reaction process, radicals 23 formed by the reaction of N-allyl-2-bromo-propanamides 21 and [Fe] undergo 5-exo cyclization to give radicals 24 which abstract Br from [Fe]Br to give products 22.

Nishikata and coworkers, in 2021, reported a photo-induced radical reaction of N-allyl-α-haloamides for the synthesis of γ-lactams. The reaction of N-allyl-α-haloamides 25 in the presence of N-Ph-phenothiazine (PTH) and MgBr₂ in DMSO under the irradiation of 365 nm LEDs at room temperature for 24 h gave products 26 in good to excellent yields (Scheme 10) [36]. The reaction first generates radicals 27 from the reaction of N-allyl amide 25 with PTH under the irradiation of LEDs. The cyclization of radicals 27 gives radicals 28 which trap the Br radical from N-allyl amides 25 to give products 26.

Clark and coworkers reported a Cu-catalyzed ATRC reaction of halo-olefins for the synthesis of nitrogen heterocycles in 2012. The reaction of N-allyl-haloacetamides 29 in the presence of CuSO₄·5H₂O, TPMA and borohydride salts at room temperature for 10 min gave products 30 in good yields (Scheme 11) [37]. The proposed mechanism suggested that [Cu^IL] produced from the reduction in [Cu^IIL] with KBH₄ reacts with 29 to form radicals 31 followed by the cyclization to give radicals 32. Final products 30 are obtained from the reaction of radicals 32 and [Cu^IILBr] along with the regeneration of [Cu^IL].

Pellizzoni and coworkers reported a myoglobin-catalyzed reaction of N-allyl-α-haloamides for the synthesis of γ-lactams in 2022. The reaction of N-allyl-α-haloamides 33 in the presence of Mb H93S (as purified protein and in whole bacterial cells), sodium ascorbate, and sodium phosphate buffer (pH 7.4) produced products 34 in good yields (Scheme 12) [38].

Initial radicals 35 produced by the reaction of N-allyl-2-bromo-propanamide 33 and [Fe^II] of Mb H93S undergo a 5-exo cyclization to give radicals 36 followed by coupling with Br radical from [Fe^III]Br to give products 34.

Diaba, Bonjoch and coworkers, in 2014, reported a Cu-mediated ATRC reaction of aminotethered dichloromalonamides for the synthesis of 2-azabicyclo[3.3.1]nonanes. The reaction of aminotethered dichloromalonamides 37 (such as carbamoyldichloroacetate-tethered alkenes and α,β-unsaturated nitriles) in the presence of CuCl, TPMA and AIBN in DCE at 60 °C for 48 h or in DMF at 80 °C for 12 h afforded products 38 in good yields (Scheme 13) [39]. Radicals 39 generated from the reaction of 37 and [Cu^IL_n]Cl undergo a 6-exo cyclization to give radicals 40 which then trap the Cl radical from [Cu^IIL_n]Cl₂ to give products 38 along with the regeneration of [Cu^IL_n]Cl.

In 2014, Ghelfi and coworkers developed a Cu-catalyzed ATRC reaction of dichloromalonamides for the synthesis of nitrogen heterocycles. The reaction of N-allyl-N-tosyl-2,2-dichlorobutanamides 41 in a mixture of AcOEt/EtOH and in the presence of CuCl/TPMA/ascorbic acid/Na₂CO₃ gave N-arylsulfonyl-halo-γ-lactams 42 in good to excellent yields (Scheme 14) [40]. Next, 3-Pirrolin-2-one 43 could be generated after the deprotection of the N-tosyl-halo-γ-lactam 42. The proposed reaction mechanism suggested that radicals 44 generated from the reaction of 41 and [Cu^IL_n]Cl undergo a 5-exo cyclization to give radicals 45 which then react with [Cu^IIL_n]Cl₂ to afford products 42 and [Cu^IL_n]Cl.

In 2015, Isse and Gennaro and their coworkers reported an electrochemical reaction of N-allyl-α,α-dichloroamides for the synthesis of halogenated nitrogen heterocycles. The reaction of N-allyl-α,α-dichloroamides 46 was carried out in a cell assembled with a Pt gauze cathode and a Pt plate anode with the appropriate cathode potential value (often 0.68 V vs. SCE). In the presence of Cu(CH₃CN)₄BF₄, TPMA, and Et₄NBF₄ in CH₃CN at 25 °C under argon, the reaction gave products 47 in good to excellent yields (Scheme 15) [41]. In this reaction process, [Cu^IL]⁺ produced from the reduction in [Cu^IIL]⁺ at the electrode surface reacts with N-allyl-α,α-dichloroamides 46 to form radicals 48 which then undergo cyclization to form radicals 49 followed by the reaction with [ClCu^IIL]⁺ to give products 47.

In 2016, Soni and Ram developed Cu-catalyzed radical cyclization reactions of N-allyl-N″-trichloro-acetylhydrazines for the synthesis of heterocyclic molecules containing two N-atoms. The reaction of N-allyl-N″-trichloroacetylhydrazines 50 in the presence of CuCl and pentamethyldiethylenetriamine (PMDETA) with DCE as solvent at refluxing for 2 h afforded a mixture of chlorinated tetrahydro-pyridazin-3-ones 51 and 1,2-diazepan-3-ones 52 in good yields (Scheme 16) [42]. Two different products were separated based on their solubility in n-hexane. The reaction of 50 with [Cu^IL]Cl first generates dichlorocarbon radical 53 via the abstraction of a chlorine atom by [Cu^IL]Cl to give [Cu^IIL]Cl₂. Radicals 53 undergo a more favorable 6-exo cyclization to give radicals 54 followed by reaction with [Cu^IIL]Cl₂ to give 6-membered products 51. Radicals 53 could also undergo less favorable 7-endo cyclization to form radicals 55 and then lead to the formation of 7-membered products 52.

2.3. N-Allyl-haloamines as Substrates

N-Allyl-haloamines are another class of substrate for ATRC that originates N-containing heterocyclic compounds. A Cu-catalyzed radical cyclization reaction of N-allyl-haloamines for the synthesis of substituted 2,4-trans-(NH)-pyrrolidines was reported by Gupta and coworkers in 2016. The reaction of 2,2,2-trichloro-ethylallyl- NH-amines 56 with CuCl and PMDETA with CH₃CN as solvent at 0 °C gave products 57 in high yields (Scheme 17) [43]. The radicals 58 generated from Cl atom transfer of 56 cyclized to form radicals 59 followed by the reaction with [ClCu^IIL]⁺ to give products 57.

A protocol of Fe-catalyzed radical cyclization reaction of cloromethyl-1,6-dienes /1,6-enynes for the synthesis of nitrogen heterocycles was reported by Tong and coworkers in 2017. The reaction of chloromethyl-1,6-dienes/1,6-enyne 60 or 61 using DPPF [1,1’-bis(diphenylphosphino)-ferrocene] as a catalyst and PhCF₃ as a solvent at 120 °C for 24 h gave products 62 or 63 in good yields (Scheme 18) [44]. In this reaction process, the abstraction of a chlorine atom from substrates 60 by DPPF leads to the formation of radicals 64 which undergo a 7-endo cyclization to form radicals 65, or a 6-exo cyclization to give radicals 66. The reaction of radicals 65 or 66 with Mⁿ⁺¹Cl afford products 62a or 62b.

Sadanandan and Gupta, in 2020, developed Cu-catalyzed radical reactions of trichloroethyl allylamines for the synthesis of nitrogen heterocycles. The reaction of trichloroethyl allylamines 67 in the presence of CuCl/PMDETA at 0 °C in MeCN under N₂ atmosphere gave products 68 in good yields (Scheme 19) [45]. While the reaction of allylamines 69 in refluxing DCE/MeCN under N₂ atmosphere afforded a mixture of products 70 and 70′. In the reaction process, radicals 71 formed from 67 via the abstraction of a Cl atom by [Cu^IL]Cl undergoing a 5-exo cyclization to give radicals 72 which then lead to the formation of products 68 after coupling with [Cu^IIL]Cl₂.

In 2019, Gupta and coworkers reported a Cu-catalyzed radical reaction of trichloroethyl-NH-enamine for the synthesis of multi-functionalized pyrroles. The reaction of trichloroethyl-NH-enamines 73 with CuCl, PMDETA and AIBN in refluxing DCE afforded products 75 in good yields (Scheme 20) [46]. The initial radicals formed via the abstraction of a Cl atom of 73 by [Cu^IL]Cl undergo a 5-endo cyclization to give radicals 76 followed by the Cl atom transfer from [Cu^IIL]Cl₂ to give products 74. Sequential dehydrochlorinative aromatization of 74 leads to the substituted pyrroles 75.

2.4. O-Allyl-halo Ethers as Substrates

There are several examples of using O-allyl-halo ethers as starting materials for ATRC to prepare O-containing heterocyclic compounds. Yu and Yang [47], in 2022, introduced a Cu-catalyzed radical reaction of unsaturated iodides for the synthesis of iodine-substituted heterocycles. The reaction of 2-allyloxy-3-iodotetrahydropyrans or tetrahydrofurans 77 in the presence of [Cu^I(N^N)(P^P)]PF₆ complexes and ascorbic acid (VC) under the irradiation of blue LEDs in a mixture of CH₃CN and H₂O or in pure water afforded products 78 in good yields (Scheme 21) [47]. The initial radicals 79 produced from the reaction of 77 under either the photo-excited [Cu^I]^* or the in situ generated [Cu⁰] species from [Cu^I]^* undergo cyclization to form radicals 80 followed by iodine transfer to give products 78.

Yoshimi and co-workers, in 2014, reported a photo-induced radical reaction of allyl-bromonaphthyl ethers for the synthesis of naphtho[b]furans. The reaction of allyl-halo-naphthyl ethers 81 in CH₃CN (or t-BuOH) under the irradiation of a 100 W high-pressure mercury lamp with a Pyrex glass filter (>280 nm) at room temperature for 3 h gave 2-halomethyl substituted naphthodihydrofuran 82 and naphtho[b]furans 83 in good yields (Scheme 22) [48]. The reaction involves the formation of triplet states of 84* from 81 under photo-irradiation followed by homolytic cleavage of C–X bond to give radicals 85 and Br radical. The 5-exo cyclization of radicals 85 gives radicals 86, followed by Br radical trapping to yield brominated products 82 which could undergo further dehydrobromination and tautomerization to give 83.

In 2016, Soni and coworkers reported a Cu-catalyzed cyclization of 2,2,2-trichloroethyl vinyl ethers for the synthesis of highly substituted 2,3-difunctionalized-4-chlorofurans. The reaction of 2,2,2-trichloroethyl vinyl ethers 87 in the presence of CuCl, and tetramethylethylenediamine (TMEDA) or PMDETA using benzene as solvent at reflux for 12–32 h gave products 89 in good yields (Scheme 23) [49]. Radicals 90, generated from 2,2,2-trichloroethyl vinyl ethers 87 via abstraction of a chlorine atom by [Cu^IL]Cl, undergo 5-endo cyclization to give radicals 91 which then lead to the formation of products 88 after trapping the Cl radical from [Cu^IIL]Cl₂. Further transformation of 88 via aromative dehydrochlorination gives substituted furans 89.

In 2018, the Tittal group reported a Cu-catalysed radical reaction of 1-(3-methyl-but-2-enyl)-naphthalen-2-yl ester for the synthesis of 7-membered lactones. The reaction of 1-(3-methyl-but-2-enyl)-naphthalen-2-yl ester 92 in the presence of CuCl/TMEDA in refluxing DCE for 5 h gave product 93 in 23% yield along with 1-(3-methyl-but-2-enyl)-naphthalen-2-ol 94 in 60 % yield (Scheme 24) [50]. Radical 95, generated from the homolytic C–Cl bond cleavage of 92, undergoes 7-exo cyclization to give radical 96, which then traps the Cl radical from [Cu^IIL]Cl₂ to give product 93.

2.5. O-Allyl-halo-hemiacetal Acetates as Substrates

The use of O- or S-allyl-halo-hemiacetal acetates as substrates for ATRC could lead to the formation of cyclic hemiacetal compounds. In 2014, Roncaglia and coworkers introduced a Cu-catalyzed reaction of O-allyl-2,2-dichlorohemiacetal acetates for the construction of cyclic acetals and γ-lactones. The reaction of O-allyl-2,2-dichlorohemiacetal acetates 97 with CuCl and PMDETA in toluene at 80 °C for 18 h afforded cyclic acetals 98 in good to excellent yields (Scheme 25) [51]. The initial radicals 100 generated from the reaction of 97 and [Cu^IL_n]Cl undergo cyclization to give radicals 101 which couple with the Cl radical from [Cu^IIL_n]Cl₂ to yield cyclic acetals 98. The cyclic acetals 98 could be readily hydrolyzed and oxidized to form γ-lactones 99.

In 2016, Gupta, Soni and their coworkers reported a Cu-promoted radical reaction of 2,2,2-trihaloethylallyl sulfides for the synthesis of highly substituted tetrahydrothiophenes. The reaction of 2,2,2-trihaloethylallyl sulfides 102 with CuCl/PMDETA in CH₃CN at room temperature gave products 103 in good to high yields (Scheme 26) [52]. Initial radicals 104 generated from the reaction of 2,2,2-trihaloethylallyl sulfides 102 with [Cu^IL]⁺ undergo 5-exo cyclization followed by the reaction with [Cu^IIClL]⁺ to give products 103.

In 2017, Gupta and coworkers reported a Cu-catalyzed radical cyclization reaction of unsaturated carbohydrate-derived chloroacetals for the synthesis of chlorinated perhydrofuro[2,3-b]pyrans. The reaction of chloroacetals 105 with CuCl/2,2’-bipyridine in refluxing dichloroehtane (DCE) under N₂ atmosphere for 4 h gave products 106 in good yields (Scheme 27) [53]. The initial radicals 107 generated from 105 via abstraction of a chlorine atom by [Cu^IL]Cl undergo 5-endo-cyclization to give radicals 108 which then react with [Cu^IIL]Cl₂ to form products 106.

2.6. Other Vinyl Derivatives as Substrates

Presented in this section are the ATRC reactions using the substrates which are not included in the previous sections. The transfer groups X could be unique carbonate, pyridinyl, xanthyl, and TEMPO-related groups. Similar to the halogen atoms, these groups are good for homolytic cleavage to generate radicals for ATRC reactions. Gevorgyan and coworkers in 2018 reported a Pd-catalyzed radical reaction of iodovinyl derivatives for the synthesis of cyclic compounds. The reaction of iodovinyl derivatives 109 in the presence of Pd(OAc)₂, DPEphos and Cy₂NMe under the irradiation of 34 W blue LEDs in benzene afforded products 110 in good to excellent yields (Scheme 28) [54]. The reaction first generates Pd-radical intermediates 111 via a SET process of vinyl iodides 109 with the active [Pd⁰L_n]^*. After 1,5-HAT (hydrogen atom transfer) of 111 to form 112 followed by a 5-exo cyclization give radicals 113, these undergo reductive elimination of [Pd⁰L_n] to give products 110.

A unique ATRC reaction involving the pyridinyl group was reported by Hong and coworkers in 2019. They developed a visible-light-induced radical reaction of N-alkenyloxypyridinium salts for the synthesis of pyridine-tethered tetrahydrofurans. The reaction of N-alkenyloxypyridinium salts 114 in the presence of 3-phosphonated quinolinone (Q2) and NaHCO₃ under the irradiation of blue LEDs at room temperature gave products 115 in good yields (Scheme 29) [55].

The initial alkoxy radicals 116 generated from N-alkoxypyridinium salts 114 via the reaction with photoexcited state [Q₂]^* undergo 5-exo cyclization to give radicals 117. Reaction of 117 with substrates 114 for the addition of pyridyl group forms radicals 118 followed by the N–O bond cleavage to give products 115. In 2020, Barriault and coworkers reported a photo-induced radical reaction of bromoalkanes for the synthesis of cyclic compounds. The reaction of unactivated bromoalkanes 119 in the presence of Au₂(μ-dppm)₂(NTf₂)₂ under the irradiation of UVA LEDs in CH₃CN/H₂O produced products 120 in good yields (Scheme 30) [56]. In the reaction process, bromoalkenes 119 react with [Au^I−Au^I]^* species 121 to form intermediates 122 followed by C–Br bond cleavage to give radicals 123 and 5-exo cyclization to form radicals 124. In the end, the products 120 are obtained from radicals 124 after Br atom abstraction.

A Cu-catalyzed radical reaction of allyl bicyclic β-lactam for the synthesis of tricyclic β-lactams has been reported by Dawra and coworkers in 2020. The reaction of allyl bicyclic β-lactam 125 under the catalysis of CuCl/PMDETA in DCE at room temperature gave products 126 or 127 in good to excellent yields (Scheme 31) [57]. Between two alkenyl groups (S-allyl and N-allyl) the competitive experiments revealed that the ATRC is more favorable to the S-allyl group than the N-allyl group. It was suggested that radicals 128 formed via the abstraction of a Cl atom of 125 by [Cu^IL]Cl undergo a 5-exo cyclization to give radicals 129 which then react with [Cu^IIL]Cl₂ to give products 126.

Shi and coworkers in 2021 introduced an interesting ATRC reaction involving carbonate radical transformation. The photo-induced radical reaction of methylenecyclopropanes tethered with carboxylic acid for the synthesis of spiro[cyclopropane- 1,2-indan]ones. The reaction of carboxylic acids tethered methylenecyclopropanes 130 and dimethyl dicarbonate (DMDC) in the presence of fac-Ir(ppy)₃ under 5 w blue LEDs in 1,4-dioxane at room temperature gave products 131 in excellent yields (Scheme 32) [58]. In the reaction process, carbonates 132 generated in situ from the reaction of carboxylic acid 130 and DMDC first form radical anions that undergo fragmentation of methyl carbonate 133 to give acyl radicals 134 followed by a 5-exo cyclization to form radicals 135. Sequential oxidation of 135 to cations 136 and nucleophilic attack by cation 133 produces products 131.

Jahn and co-workers reported a TEMPO-related ATRC of α,γ-dioxygenated amides for the synthesis of γ-lactams. The reaction of α,γ-dioxygenated amides 137 in t-BuOH under the irradiation of microwave at 150 °C for 1 h followed by the treatment with TBAF in THF gave products 138 in good to excellent yields (Scheme 33) [59]. The proposed reaction mechanism suggests that radicals 139 generated from N-allyl amides 137 undergo a 5-exo cyclization to give radicals 140 which then couple with OTMP radical to form 141 and then products 138 after OTMS deprotection.

Marchese and coworkers, in 2022, developed a photo-induced radical reaction of allyl 2-iodobenzenes for the synthesis of iodinated heterocyclic compounds. The reaction of allyl 2-iodobenzenes 142 in the presence of [Pd(allyl)Cl]₂, DPEPhos and K₂CO₃ in toluene under the irradiation of blue LEDs gave products 143 in good yields (Scheme 34) [60]. The initial radicals 144 produced by photo reaction of 142 with [Pd⁰]^* undergo a 5-exo cyclization to form 145 followed by iodine transfer to give product 143.

Chen and Wang and coworkers, in 2022, introduced a xanthate-involved ATRC reaction of unactivated olefins for the synthesis of various nitrogen heterocycles such as γ-lactams, δ-lactams, pyrrolidines, indolones, quinolinones, and fused polycyclic compounds. The reaction of N-xanthylamides 146 in CH₂Cl₂ under the irradiation of 24 W 400 nm LEDs at room temperature gave products 147 or 148 in good to excellent yields (Scheme 35) [61]. It is worth mentioning that the xanthate-transfer reaction proceeded without photo-catalyst and additive. The proposed reaction mechanism suggested that visible light-induced N−S bond homolysis of substrates 146 gives xanthate radical 149 and amidyl radicals 150. The 5-exo or 6-endo cyclization of 150 gives radicals 151 and 152, respectively. Finally, the coupling of 151 or 152 with xanthates 146 affords products 147 or 148.

Yu and coworkers developed a Cu-catalyzed radical reaction of unactivated alkyl bromides for the synthesis of five-membered heterocyclic rings in 2023. The reaction of unactivated alkyl bromides 153 in the presence of CuBr and Me₆TREN gave products 154 in good to excellent yields (Scheme 36) [62]. It was suggested that radicals 155 produced from the reaction of alkyl bromides 153 and [Cu^I] undergo a 5-exo cyclization to give radicals 156 that then lead to the formation of products 154 after coupling with [Cu^II]Br.

3. Second Functionalization with Y via Radical Coupling

Presented in this section are the reactions in which the second functionalization is accomplished by coupling with radical Y (Scheme 37). Different from the ATRC in which the X radical is from the same substrate for cyclization, the Y radical is generated from a different substrate. As shown in Scheme 37, radicals I-B generated from the homolytic cleavage of X–C bond undergo cyclization to form radicals II-B followed by coupling with radical Y generated from a different reactant to give the products. The reactions presented in this section are classified based on the substrates including alkenyl oximes, amino-substituted alkenes, alkynes, and allenes, halo-substituted alkenes, alkynes and allenes as well as other alkenes and allenes. There is a wide range of Y radicals that could be used for the second functionalization. The Y groups presented in this section include halogen atoms and NO, CF₃, Bpin, 2-azaallyl, lauroyl, alkenyl, N₃, arylthiomethyl, ketyl, and TEMPO-related groups.

3.1. Alkenyl Oximes as Substrates

There are several examples using alkenyl oximes as substrates for the generation of iminoxyl radicals for cyclization and sequential difunctionalization reactions. Han and coworkers, in 2014, reported a radical cyclization reaction of unsaturated ketoximes for the synthesis of heterocyclic compounds. The reaction of ketoximes 157 in the presence of tert-butyl nitrite (TBN) in CH₃CN at room temperature for 0.5 h, followed by the addition of Et₃N and heating at 80 °C for 0.5 h afforded oxime featured 4,5-dihydroisoxazoles 158 or cyclic nitrones 159 in good to excellent yields (Scheme 38) [63]. In this reaction, TBN is used as the iminoxyl radical initiator and the carbon radical trap. Initially, the reaction of ketoximes 157 with TBN generates unsaturated iminoxyl radicals (O-atom radical 160 and N-atom radical 161) which undergo 5-exo cyclization to form radicals 162 (n = 0) and 163 (n = 1), respectively. Radical trapping of 162 or 163 with TBN affords intermediates 164 or 165 which could be further converted to products 158 or 159. The dimerized 158’ generated from intermediates 164 was isolated and its structure was confirmed by a single-crystal X-ray diffraction study.

Zhang and coworkers, in 2018, reported a Ru-catalyzed radical reaction of alkenyl oximes for the synthesis of 5-cyanated isoxazolines. The reaction of alkenyl oximes 166 and TBN catalyzed with RuCl₂(p-cymene)]₂ and MgSO₄ in CH₃CN at room temperature for 4 h gave 5-cyanated isoxazolines 167 in good to high yields (Scheme 39) [64]. In the reaction process, TBN acts as an oxidant and a nitrogen source to avoid the use of toxic radical initiators or cyanide reagents. The initial oxime radicals 168 produced via oxidization of alkenyl oximes 166 with TBN undergo 5-exo cyclization followed by the coupling with t-BuO radical to give intermediates 169 which could be tautomerized to form intermediates 170. Ru-Catalyzed reduction in 170 gives final products 167.

In 2016, Kang and coworkers introduced a similar radical reaction of alkenyl oximes for the synthesis of halo-isoxazolines. The reaction of alkenyl oximes 171 with TBN as a dual oxidant and AlCl₃, CBr₄ or CHI₃ as a halogen source in THF/H₂O for 20 min gave halo-isoxazolines 172 in moderate to good yields (Scheme 40) [65]. In this reaction, the oximes 171 were oxidized by TBN to yield the iminoxyl radicals 173 with the generation of NO and tert-butanol, followed by 5-exo cyclization to give the radical intermediates 174. Simultaneously, TBN oxidizes the Cl-anion to the chlorine radical. Next, the final products 172 were obtained from radicals 174 by combining them with the chlorine radical. Otherwise, the cations 175 were formed by oxidization of TBN, followed by reaction with Cl-anion to access the products 172.

In 2017, Hu and coworkers developed Cu-catalyzed radical reaction of allylic oximes for the synthesis of trifluoromethylated isoxazolines. The reaction of allylic oximes 176 and TMSCF₃ in the presence of trichloroisocyanuric acid (TCCA), CuOAc, 1,10-phenanthroline (1,10-phen) and CsF in CH₃CN at room temperature for 1–10 h afforded products 177 in good to excellent yields (Scheme 41) [66]. In the reaction process, radicals 178 generated from TCCA abstract H atom from allylic oximes 176 to form radicals 179 which undergo 5-exo cyclization to give radical 180. The trapping of CF₃ radical derived from TMSCF₃ with 180 generates trifluoromethylated isoxazolines 177.

In 2019, Xu and Li and coworkers reported a Cu-catalyzed radical reaction of unsaturated ketoximes for the synthesis of 5-halomethyl isoxazolines. The reaction of ketoximes 181 and halo reagents 182 (such as diethyl bromomalonate, N-chlorosuccinimide, and N-iodosuccinimide) in the presence of Cu(OTf)₂, 1,10-Phen and Na₂CO₃ in CH₃CN at 80 °C for 0.5 h produced 5-halomethyl isoxazolines 183 in good to excellent yields (Scheme 42) [67]. The iminoxyl anions 184 formed by the deprotonation of ketoximes 181 with a base undergo SET with Cu^II to generate iminoxyl radicals 185. Subsequent radical cyclization of 185 to form 186 followed by halogen atom transfer with Br–Y 182 originates the desired products 183.

3.2. Amino-Substituted Alkenes, Alkynes, and Allenes as Substrates

Amino-substituted alkenes, alkynes, and allenes could be used as the substrates to generate N-radicals for cyclative difunctionalization reactions. In 2013, Chemler and coworkers introduced a Cu-catalyzed enantioselective radical reaction of alkenyl sulfonamides for the synthesis of chiral indolines and pyrrolidines. The aminooxygenation reaction of alkenyl sulfonamides 187 with the use of TEMPO as the oxygen source and under the catalysis of Cu(OTf)₂ and (R,R)-Ph-Box in PhCF₃ gave desired products 188 in good to excellent yields and high enantioselectivity (Scheme 43) [68]. The reaction kinetics showed a first-order dependence in the sulfonamide substrate and the Cu−bis(oxazoline) complex and zero order in TEMPO. In the reaction process, (R,R)-Ph-Box)/Cu(OTf)₂ complex 189 reacts with 187 to produce N−Cu^II intermediates 190 which then leads to the formation of 191. Homolysis of 191 to give 192 followed by trapping with TEMPO affords products 188. The reactive Cu^II species 189 is regenerated by oxidization of the Cu^I species 193 with TEMPO to complete the catalytic cycle.

Wirth and coworkers reported an electrochemical flow reaction of carbamates for the synthesis of isoindolinone derivatives in 2017. The reaction of carbamates 194 and TEMPO using benzyltrimethylammonium hydroxide ([BnNMe₃]⁺OH⁻) as the supporting electrolyte in an electrochemical flow micro-reactor under the optimized reaction conditions (3 F mol⁻¹, 24 mA, 1–2 V) gave products 195 in good yields (Scheme 44) [69]. The isoindolinone products 195 could be used for the following two subsequent functionalizations: (1) elimination of the TEMPO moiety with Backpressure regulator to yield alkenes 196, and (2) reduction in the N–O bond with Zn and acetic acid to yield corresponding alcohols 197. In this reaction process, the TEMPO cation 198 reacts with carbamates 194 generating TEMPO radical 199 and nitrogen radicals 200. Cyclization of radicals 200 to form 201 followed by a radical trapping with TEMPO gives products 195.

In 2023, Renzi and coworkers reported a photo-induced radical reaction of N-(allenyl)sulfonylamides for the synthesis of 2-(1-chlorovinyl)pyrrolidines. The blue LEDs irradiated reactions of N-(allenyl)sulfonylamides 202, N-chlorosuccinimide (NCS) and K₂CO₃ under the catalysis of [Ru(bpy)₃](PF₆)₂ using anhydrous PhCH₃ and HCO₂CH₃ as a co-solvent for 21 h gave products 2-(1-chlorovinyl)pyrrolidines 203 in good yields (Scheme 45) [70]. After the initial deprotonation of allenes 202 with a base to form 204, there are two different pathways for the formation of radicals N-centered radicals 205. In path a, radicals 205 are generated from the oxidation of 204 with the photoexcited state of the Ru-catalyst. In the path b, reaction of 204 with NCS to form 206 followed by the photodissociation of Cl gives 205. The 5-exo cyclization of radical 205 affords vinyl radical 207 followed by radical trapping to give final 2-(1-chlorovinyl)pyrrolidines 203.

3.3. Halo-Substituted Alkenes, Alkynes and Allenes as Substrates

Halogenated alkenes, alkynes and allenes are good substrates to generate carbon radicals for cyclative difunctionalization reactions. Liang and coworkers, in 2020, introduced a visible-light-induced radical reaction of alkyl bromides or alkyl iodine for the synthesis of heterocyclic compounds. The reaction of alkyl bromides or iodines 208 and KI with Pd(PPh₃)₄ as a photo-catalyst and potassium carbonate as a base under the irradiation of blue LEDs afforded heterocyclic compounds 209 in moderate yields (Scheme 46) [71]. Under the conditions of using Pd(PhCN)₂Cl₂ as a catalyst and potassium carbonate as a base, the reaction with diboron reagents gave borylated products 210 in moderate yields. In the reaction process for products 209, the [Pd⁰]^*-promoted homolytic cleavage of the aryl C−Br bond of 208 yields radicals 211 which undergo 5-exo cyclization to form radicals 212 followed by iodiozation with [Pd^I]I to give products 209. For the borylation reaction, recombination of radicals 212 with [Pd^I]Br gives Pd-complexes 213 which undergo transmetalation with bis(pinacolato)diboron to form Pd-complexes 214. Finally, the reductive elimination of Pd-cat of 214 affords borylated products 210.

In 2023, Yao and coworkers reported an N-heterocyclic carbene (NHC)-catalyzed radical reaction of α-bromo-N-cinnamylamides for the synthesis of 2-pyrrolidinone derivatives. The reaction of α-bromo-N-cinnamylamides 215 and aldehydes 216 in the presence of NHC precursor NHC-1 and Cs₂CO₃ in DCE at 40 °C for 13–48 h afforded 2-pyrrolidinone derivatives 217 in good to excellent yields (Scheme 47) [72]. The NHC catalyst generated by the reaction of catalyst precursor NHC-1 with Cs₂CO₃ couples with aldehyde 216 to form intermediates 218 which are then deprotonated with Cs₂CO₃ to give enolate intermediates 219. A process of SET of α-bromo-N-cinnamylamides 215 with 219 produces the radical zwitterionic intermediates 220 and radical intermediates 221. The 5-exo cyclization of the radicals 220 gives 222 followed by radical coupling with the radicals 221 to provide 223 and the last step of NHC catalyst elimination to give products 217.

Zhou and coworkers, in 2015, reported a visible-light-induced radical reaction of trifluoroacetimidoyl chlorides for the synthesis of 2-trifluoromethyl-3-acylindoles. The reaction of trifluoroacetimidoyl chlorides 224 in the presence of Ru(phen)₃Cl₂, (p-MeOC₆H₄)₃N (Ar₃N), and H₂O in DMSO under the irradiation of 5 W blue LEDs at room temperature gave products 225 in good to excellent yields (Scheme 48) [73]. The proposed reaction mechanism suggested that imidoyl radicals 226 produced by the C–Cl bond cleavage of trifluoroacetimidoyl chlorides 224 undergo a 5-exo cyclization to form vinyl radicals 227 which then go through two different pathways to generate 2-CF₃ indoles 225. For the favorable pathway (path a), the reaction of vinyl radicals 227 and trifluoroacetimidoyl chlorides 224 afford vinyl chlorides 228 followed by hydrolysis to give enols 229 and then isomerization to give 225. While in the less favorable pathway (path b), vinyl cations 230 are formed by the oxidation of radicals 227 with excited [Ru(phen)₃]^2+* or Ar₃N radical cation followed by trapping with H₂O to yield enols 229 and then products 225 after isomerization.

In 2018, Zhao and coworkers introduced a Cu-catalyzed radical reaction of acetylenic iodides for the synthesis of functionalized exocyclic alkenes. The reaction of acetylenic iodides 231 and B₂pin₂ in the presence of CuCl and t-BuOLi in DMF at room temperature for 4 h gave products 232 in good yields (Scheme 49) [74]. The proposed reaction mechanism suggested that the reaction of acetylenic halides 231 with Cu^I–Bpin followed by a 5-exo cyclization affords intermediates 233 which then react with the Cu^II species to give borylated products 232.

A visible-light-induced radical reaction of aryl iodides for the synthesis of benzofuran-, indole-, and benzothiophene-based benzylic gem-diboronates was reported by the Hashmi group in 2020. The reaction of aryl iodides 234 and B₂Pin₂ under the irradiation of blue LEDs in the presence of [Au₂(μ-dppm)₂](OTf)₂ and Na₂CO₃ in MeCN for 15 h afforded products 235 in good to excellent yields (Scheme 50) [75]. The photoactivated Au-complex promotes the homolytic cleavage of the C−I bond of aryl iodide 234 to give aryl radicals 236 which undergo 5-exo cyclization followed by radical trapping to give vinyl boronates 237. Formation of benzyl cations 238 by electrophilic borylation of boronates 237 with Bpin−I or Bpin−OCO₂Na followed by rapid β-H elimination gives products 235.

The Guo group reported a visible-light-induced radical reaction of alkyne-containing aryl iodides for the synthesis of 1,4-dicarbonyl compounds. The reaction of alkyne-containing aryl iodides 239, TEMPO and 4-methoxythioxanthone under the irradiation of purple LEDs using acetone/DCM as solvent gave products 240 in good to excellent yields (Scheme 51) [76]. Under the irradiation of purple LEDs, the photosensitizer 4-methoxythioxanthone converts substrates 239 to triplet state 239^* to form aryl radicals for 5-exo cyclization followed by trapping with TEMPO to afford intermediates 241. The photo-excited triplet state intermediates 241^* undergo a single-electron reduction and coupling with I⁻ to give intermediates 242 followed by removal of iodine radical and biradical coupling to provide 1,4-dicarbonyl compounds 240.

A radical reaction of 2-iodoaryl-allenyl ethers for the synthesis of benzofuran derivatives was reported by the Walsh group in 2019. The reaction of 2-iodoaryl-allenyl ethers 243 and ketimines 244 in the presence of LiN(SiMe₃)₂ in DME for 12 h gave products 245 in good to excellent yields (Scheme 52) [77]. In the reaction process, 2-azaallyl anions 246 generated from ketimines 244 serve as a “super electron donor” (SED). The SET of 246 to aryl iodides 243 generates aryl radicals 248 which undergo 5-exo cyclization to form 2-azaallyl radicals 249 followed by trapping radicals 247 to afford products 245. The same group extended the scope of this reaction using 2-iodobenzyl allenyl ethers 250 as substrates for the synthesis of substituted isochromenes 251 (Scheme 53) [78].

3.4. Other Functionalized Alkenes and Allenes as Substrates

In addition to the substrates presented above, compounds used for the formation of initial radicals could be used as the source for the second functionalization. Xu and Kakaei in 2013 reported a radical reaction of alkyl N-allylcarbamodithioates for the synthesis of (2-alkylthiothiazolin-5-yl)methyl dodecanoates. The reaction of alkyl N-allylcarbamodithioates 252 and dilauroyl peroxide (DLP) in refluxing DME for 4–7 h gave products 253 in good yields (Scheme 54) [79]. The heating of DLP gives lauroyl radical 254 followed by decarboxylation to form undecyl radical 255. H-abstraction of 255 from N-allylcarbamodithioates 252 generates thiyl radicals 256 which undergo 5-exo cyclization to yield (2-alkylthiothiazolin-5-yl)-methyl radicals 257. Final products (2-alkylthiothiazolin-5-yl)methyl dodecanoates 253 are obtained from the reaction of radicals 257 with DLP along with regeneration of the lauroyl radical 254.

In 2020, Riant and coworkers reported a radical electrocyclization of potassium 3-(diallylamino)-3-oxopropanoate for the synthesis of 4-substituted pyrrolidin-2-ones. In Teflon half-cells equipped with platinum-plated electrodes, the reaction of potassium 3-(diallylamino)-3-oxopropanoates 258 in the presence of KOH and RCOOH with MeOH as solvent gave 4-substituted pyrrolidin-2-ones 259 in good yields (Scheme 55a) [80]. The application of this method for continuous flow electrochemical reaction in a loop-reactor setup (equipped with a 5 mL container) allowed for an excellent productivity of 0.40 g/(h·mL) and afforded 2-pyrrolidinone 259a in 81% yield (Scheme 55b) [81]. The product could be used for the synthesis of Brivaracetam in 23% yield. For the synthesis of 259, radicals 260 generated via Kolbe decarboxylation of 258 undergo 5-exo cyclization followed by coupling of Et radical with 261 to give the final products.

In 2022, Castle and coworkers developed a protocol of thermal and microwave-promoted radical cyclization of O-aryloximes for the synthesis of functionalized pyrrolines. The reaction was carried out using O-aryloximes 262 and the radical traps Y−Z in PhCF₃ at 120 °C for 1−2 h, and the products functionalized pyrrolines 263 were obtained in good yields (Scheme 56) [82]. The reactions could be triggered by either microwave irradiation or conventional heating in an oil bath. Initially, the iminyl radicals 264 are generated by direct homolysis of the weak N−O bond of O-aryloximes 262, which could be promoted by either microwave irradiation or conventional heating. Subsequently, radicals 265 are formed by a 5-exo radical cyclization of radicals 264, followed by radical trapping to give the final functionalized pyrrolines 263.

In 2022, Chemler and coworkers reported a Cu-catalyzed radical reaction of alkenols for the synthesis of arylthiomethyl-substituted cyclic ethers. The reaction of alkenols 266 and diaryl disulfides in the presence of Cu(OTf)₂, (S,S)-t-Bu-Box, MnO₂ and K₂CO₃ in PhCF₃ at 120 °C for 14 h afforded arylthiomethyl substituted cyclic ethers 267 in moderate to good yields and high enantioselectivity (Scheme 57) [83]. It should be mentioned that the target compound was obtained in a lower yield without an external oxidant (MnO₂ or O₂). The proposed reaction mechanism suggests that the enantioselective route (path a) is lower in energy than the competing racemic route (path b). First, C−O bond formation via enantioselective oxycupration of 266 affords intermediate 268 followed by C−[Cu] homolysis to give radical intermediate 269. The formation of C−S bond via coupling of 269 with PhS radical gives oxysulfenylated product 267.

A photo-promoted radical cyclization of alkenes for the synthesis of benzocyclic boronates was reported by the Li group in 2023. The reaction of allyl aryldiazonium salts 270 and bis(catecholato)diboron (B₂cat₂) using methylene blue as catalyst under the irradiation of 30 W blue LEDs in dimethylacetamide (DMA) for 2 h at room temperature followed by the treatment with pinacol gave benzocyclic boronates 271 in good yields (Scheme 58) [84]. The proposed mechanism suggests the generation of an aryl radical 272 from the diazonium salt 270 either by heat-induced decomposition (path a) or by SET through an excited photocatalyst (path b). The 5-exo cyclization of 272 forms benzocyclic alkyl radical 273 followed by the boron-transfer with 274 to give the borylated product 275 and the radical anion 276. Alcohol exchange between 275 and pinacol gives the final product 271.

In 2023, Ye and coworkers developed a protocol of photoredox N-heterocyclic carbene catalyzed radical cyclization of alkene-tethered α-imino-oxy acids for the synthesis of substituted 3,4-dihydro-2H-pyrroles. The reaction was carried out using alkene-tethered α-imino-oxy acids 277 and acyl imidazoles 278 with N-Mes-substituted triazolium (preNHC, Mes = 2,4,6-trimethylphenyl) as the catalyst and 2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile (4CzIPN) as photocatalyst in the presence of Na₂CO₃ in DMSO under irradiation of blue LEDs at room temperature for 24 h, and the products substituted 3,4-dihydro-2H-pyrroles 279 were obtained in moderate to good yields and with good to high diastereoselectivities (Scheme 59) [85]. Initially, the iminyl radical intermediates 281 were generated via oxidization of the carboxylate anions 280 of α-imino-oxy acids 277 with the excited photosensitizer 4CzIPN^*, followed by 5-exo cyclization to give the dihydropyrrole-derived C-radicals 282. In the meantime, the acyl azoliums 283 were formed via the addition of acyl imidazoles 278 with in situ generated free NHC, followed by reduction with 4CzIPN^•− to give the ketyl radicals 284 and 4CzIPN. Next, the intermediate adducts 285 were provided by the radical coupling of the radicals 282 with the radicals 284, followed by fragmentation to deliver the final iminoacylation products 279 and release the NHC catalyst for the catalytic cycle.

In 2021, Schomaker and coworkers developed a protocol of photo-promoted radical cyclization of allenes for the synthesis of pyrrolidin-2-one derivatives. The reaction was carried out using allenes 286 and TEMPO in the presence of K₂CO₃ under the irradiation of blue LEDs with MeCN as solvent, and the products pyrrolidin-2-one derivatives 287, 288 and 289 were obtained in moderate yields (Scheme 60) [86]. Initially, radical 290 was generated from allene 286 under irradiation of visible light, followed by 5-exo cyclization to give radical 291. Then, product 288 was formed via radical trapping, followed by H exchange to give the enone 289. Meanwhile, the O-centered radical 292 was produced by radical hemolysis of 288, followed by electron transfer to give the C-centered radical 293. Finally, product 287 was obtained by radical trapping of radical 293.

4. Second Functionalization with Metal Complexes

In this section, examples of the use of metal complexes for the second functionalization are presented (Scheme 61). In addition to Cu complexes, Pd, Ni, and Co complexes have been developed for the coupling reactions.

Chemler and coworkers reported a protocol of Cu-catalyzed radical reaction of alkyne-tethered Cbz-protected hydroxylamines for the synthesis of functionalized isoxazolidines in 2017. The reaction of alkyne-tethered Cbz-protected hydroxylamines 294 and amine sources in the presence of Cu(2-ethylhexanoate)₂, 2,6-di-t-Bu-4-Me-pyridine, MnO₂ and 4Å M.S. in DCE at 85 °C for 24 h gave isoxazolidines 295 in good yields (Scheme 62) [87]. It should be mentioned that sulfonamides, anilines, piperidine, morpholine and benzamide could serve as the external amine source. The proposed reaction mechanism suggests that the reaction of 294 with Cu^II leads to the formation of Cu^II-complexes 296, which participate in 5-exo cyclization to form 297 intermediates, followed by homolysis of the C−Cu^II bond to give 298. The reactions of 298 with Cu^II and amine give Cu^II-complex 299 which then leads to the formation of isoxazolidines 295 after reductive elimination of the Cu^I catalyst.

Han and coworkers, in 2017, reported a radical reaction of unsaturated ketoximes for the synthesis of isoxazolines and cyclic nitrones. The reaction of unsaturated ketoximes 300 in the presence of tert-butyl hydroperoxide (TBHP), Cu-X and PMDETA in CH₃CN at room temperature for 12 h gave 301 in good yields (Scheme 63) [88]. In the reaction process, t-BuO radical derived from TBHP reacts with oximes 300 to form iminoxyl radicals which have resonance structures 302 and 303. Radicals 302 or 303 undergo O-radical 5-exo cyclization (n = 0) or N-radical 5-exo cyclization (n = 1) to form radicals 304 or 305 which then interact with LCu^II(OH)CN to generate Cu^III species 306 or 307. Finally, products 301a or 301b are obtained by reductive elimination of Cu^III from 306 or 307 and the LCu^ICN species is regenerated.

A Cu-mediated radical reaction of β,γ-unsaturated hydrazones for the synthesis of functionalized pyrazolines was reported by Li and coworkers in 2018. The reaction of β,γ-unsaturated hydrazones 308 and M–X (M = Na, K; X = N₃, Cl, Br, I, SCN) and Cu(OAc)₂ in CH₃CN provided products 309 or 310 in good to high yields (Scheme 64) [89]. In the reaction process, HAT of β,γ-unsaturated hydrazones 308 generates N-radicals which coordinate with Cu^II to form complexes 311. Reductive elimination of Cu^II of 311 followed by a radical cyclization give radicals 312 which couple with Cu^I and M–X to provide Cu^II complexes 313 and then products 310 after reductive elimination of the Cu^I catalyst.

Zhu and coworkers, in 2019, introduced a Cu-catalyzed radical reaction of unsaturated oxime esters for the synthesis of 2-halomethyl pyrrolines. The reaction of γ, δ-unsaturated oxime esters 314 and halide salts (such as KI, KBr and KCl) and Cu(OAc)₂ in CH₃CN at 120 °C for 2.5 h gave 2-halomethyl pyrrolines 315 in good yields (Scheme 65) [90]. The proposed reaction mechanism suggested that iminoxyl radicals 316 generated from oxime esters 314 undergo 5-exo cyclization followed by coordination with Cu^IIIOBz to form complexes 317 followed by reductive elimination to afford products 315.

In 2019, Yoshikai and coworkers reported a Co−N-heterocyclic carbene catalyzed radical reaction of tosylamide-tethered bromo-alkenes for the synthesis of 3-(arylmethyl)pyrrolidine derivatives. The reaction of tosylamide-tethered bromoalkenes 318 and aryl N−H imines 319 in the presence of CoBr₂, NHCs bearing cyclohexylethyl groups (L) and t-BuCH₂MgBr in THF for 12 h afforded products 320 in good yields (Scheme 66) [91]. In the reaction process, t-BuCH₂Co^I 321 is generated from the reaction of Co^IL_nBr₂ and the Grignard reagent t-BuCH₂MgBr. It then reacts with N−H imines 319 and t-BuCH₂MgBr to give Co^II complexes 322 and then reacts with bromoalkene 318 to form complex pairs 323 which undergo 5-exo cyclization and transmetalation with the Grignard reagent to give radical complex pairs 324 and then 325. Products 320 are generated from 325 after reductive elimination of the Co catalyst and hydrolysis of the MgBr moiety.

In 2020, Shen, Han and their coworkers reported a metal-catalyzed radical reaction of iodoalkyl-tethered unactivated alkenes for the synthesis of a wide variety of cyclic compounds, including substituted cyclopentanes, furans, pyrrolidines, octahydro-1H-indenes, octahydro-benzofurans, hexahydro-4H-furo[2,3-b]pyrans, and hexahydro-furo[2,3-b]furans. The reaction of iodoalkyl-tethered alkenes 326 in the presence of In powder and Co(acac)₂ at 60 °C for 24 h in THF followed by the treatment with ArI in the presence of Pd(PhPh₃)₄ and LiCl in DMA at 100 °C for 12 h gave products 327 in moderate to good yields (Scheme 67) [92]. The proposed reaction mechanism suggested that Co^IL_nX converts olefin-tethered alkyl iodides 326 to alkyl radical anions 328 and then alkyl radical 329 after elimination of iodine anion. Cyclization of radicals 329 followed by radical trapping with In^IX gives alkyl indium reagent 330 which then undergoes Pd-catalyzed cross-coupling with aryl iodides to form products 327.

Zhu and coworkers reported a metal-catalyzed radical reaction of unactivated alkenes for the synthesis of SCN-substituted pyrazolines. The reaction of alkenes 331, NH₄SCN, Co(acac)₂, K₂S₂O₈, and NaHCO₃ in DMSO at room temperature for 12 h gave products 332 in good to excellent yields (Scheme 68) [93]. In the reaction process, ketoximes 331 are deprotonated with a base and oxidized by Cu^II to iminoxyl radicals 333 for 5-exo cyclization followed by the reaction with Cu^IIX₂ to form the Cu^III complexes 334. The reactions of 334 with NH₄SCN followed by reductive elimination afford products 332.

Wang and coworkers reported a Cu-catalyzed radical reaction of unsaturated ketoximes for the synthesis of cyclic nitrone products in 2021. The reaction of ketoximes 335 and morpholino benzoates in the presence of CuCl and 1,1-binaphthyl-2,2-diyl hydrogen-phosphate (BNPA) with DCE as a solvent, and the cyclic nitrone gave products 336 in good yields (Scheme 69) [94]. In the synthesis of 336a, Cu^II complex 337 generated from morpholino benzoate and Cu^ILn reacts with ketoximes 335 (n = 1) to form radicals 338 via oxidative SET. Cyclization of 338 followed by coupling with OBz radical and then reductive elimination give final products 336a.

An Ir and Cu dual-catalysts-promoted photo reaction of oxime of allyl alcohols for the synthesis of functionalized oxazolines was developed by the Nagib group in 2021. The reaction of oxime 339 derived from allyl alcohols with Ir[dF(CF₃)ppy]₂(dtbbpy)PF₆ and Cu(OTf)₂ in the presence of bisoxazoline and nucleophiles such as CN, SCN, N₃, vinyl, allyl and under the irradiation of blue LEDs for 18 h in 20:1 MeCN/DMA, gave functionalized oxazolines 340 in moderate to good yields (Scheme 70) [95]. The functional oxazolines 340 could be hydrolyzed with HCl to β-amino-γ-cyano alcohols.

A dual catalytic mechanism was proposed for this reaction. Oxime 339 undergoes [Ir^III]^*-catalyzed homolysis to form radicals 341 that react with LCu^INu(X) 342 to give Cu^II complex 343. The 5-exo cyclization of N-centered radicals 343, followed by radical trapping, yields Cu^III species 344, which form products 340 after reductive elimination of the CuI catalyst.

A Pd-catalyzed radical reaction of N-(2-bromobenzoyl)indoles for the synthesis of 2,3-disubstituted indolines was introduced by the Sharma group in 2020 (Scheme 71) [96]. The reaction of N-(2-bromobenzoyl)indoles 345 and styrenes with Pd(PPh₃)₄, Xantphos and Cy₂NMe in N-methyl-2-pyrrolidone (NMP)/DCE under the irradiation of blue LEDs for 24 h gave 2,3-disubstituted indoline derivatives 346 in moderate to good yields and good to excellent diastereoselectivities. The proposed mechanism indicated that aryl radicals 347 produced via a SET reduction in aryl bromides 345 undergo 5-exo radical cyclization followed by the addition of styrenes to give hybrid alkyl [Pd^I] radicals 348. The radicals 348 have equilibrium structures 349 which undergo β-H elimination to give products 346.

In 2022, Cárdenas and coworkers reported a Ni-catalyzed radical reaction of allylamines and acryl-amides containing an active ester group for the synthesis of nitrogen heterocycles. The reaction of allylamines or acryl-amides 350, alkylzinc or arylzinc bromides, Ni(Py)₄Cl₂ and (S)-s-Bu(PyBox) in THF at room temperature for 16 h afforded pyrrolidines and pyrrolidinones 351 in good yields (Scheme 72) [97]. In this reaction, [RNi^IL_n] complexes 352 produced by the reaction of Ni(py)₄Cl₂ and RZnBr undergo SET with esters 350 to form radical anions 353 and [RNi^IL_n]⁺ complexes 354. Homolytic N−O bond cleavage of radical anions 353 followed by decarboxylation gives radicals 355 which undergo 5-exo cyclization to form 356. Further reaction of 356 with 354 and Pht⁻ originates [Ni^III] complexes 357. Products 351 are obtained by reductive elimination of complexes 357 while the [Ni^I] complex 358 could react with RZnBr to regenerate the [RNi^IL_n] complexes 352 for the catalytic cycle.

5. Second Functionalization with Y of Neutral Molecules

Presented in this section are the reactions in which the second functionalization is accomplished by reacting with neutral molecules Y followed by a reduction in the resulting radicals to anions and then deprotonation to give the final products (Scheme 73). Alkenes, alkynes, arenes, molecular oxygen (O₂), sulfur dioxide (SO₂), 2-isocyanobiaryl, CO, B₂(OH)₄, and glycine derivatives could serve as the neutral molecules for the second functionalization reactions.

5.1. Alkenes, Alkynes and Arenes as Y

There are several examples of using alkenes, alkynes and arenes for the second functionalization reactions. In 2016, Kang and coworkers reported a radical reaction of ω-iodoalkenes for the synthesis of heterocyclic compounds. The reaction of ω-iodoalkenes 359 and α,β-unsaturated carbonyl compounds 360 in the presence of Fe(CO)₅ and 1,10-phen monohydrate in CH₃CN for 24 h gave products 361 in good to excellent yields (Scheme 74) [98]. The proposed reaction mechanism suggests that complex 362, generated from Fe(CO)₅ and 1,10-phen, reacts with alkyl iodides 359 to form alkyl radical intermediates 363 which undergo 5-exo cyclization. Subsequent radical addition to the β-C in the α,β-unsaturated carbonyl compound 360 produces the α-carbonyl radicals 365 and then products 361.

A Cu-catalyzed asymmetric reaction of 2-vinylbenzyl alcohols for the synthesis of phthalans was reported by Chemler and Chen in 2018. The reaction of 2-vinylbenzyl alcohols 366 and 1,1-diarylethylene in the presence of Cu(OTf)₂, (S,S)-t-Bu-Box, K₂CO₃, and MnO₂ in PhCF₃ at 120 °C for 24 h gave phthalan products 367 in good to high yields and enantioselectivity (Scheme 75) [99]. Radicals 368 generated from benzylalcohols 366 coordinate with Cu^II to give intermediates 369 and lead to the formation of radicals 370 after a 5-exo cyclization. The addition of 370 to arylethylenes gives benzylic radicals 371 followed by oxidation and H-elimination to afford products 367.

Glorius and coworkers, in 2020, reported a visible-light-induced radical reaction of prenylated 2-bromophenols for the synthesis of substituted dihydrobenzofurans. The reaction of 2-bromophenols 372 and styrenes with Pd(PPh₃)₄ as photo-catalyst, xantphos as an auxiliary ligand, and potassium carbonate as a base, and 1,4-dioxane as a solvent and under irradiation of blue LEDs gave products 373 in good to excellent yields (Scheme 76) [100]. In the reaction process, photo-excited [Pd⁰]^* induces the homolytic cleavage of aryl C−Br bond of 372 to form radicals 374 for the subsequential 5-exo cyclization to give radical intermediates 375. The addition of radicals 375 to styrene derivatives followed by substituted dihydrobenzofurans 373 was obtained via β-H elimination of the intermediates 376, and the photo-catalyst Pd⁰ was regenerated for the catalytic cycle.

In 2021, Gryko and coworkers introduced a vitamin B₁₂-catalyzed radical reaction of bromoalkenes for the synthesis of substituted pyrrolidines and piperidines. Under the irradiation of blue LEDs, the vitamin B₁₂-catalyzed reaction of bromoalkenes 377 and electrophilic olefins in the presence of Zn and NH₄Cl in MeOH for only 15 min afforded substituted pyrrolidines 378 in low to good yields (Scheme 77) [101]. The reaction of 377 with Co^I which is derived from vitamin B₁₂ leads to the formation of Co-complexes 379 and radicals 380 for 5-exo cyclization to form radicals 381. The addition of radicals 381 to an electron-deficient olefin followed by a single electron reduction with the Zn affords products pyrrolidines 378.

A photo and Pd-catalyzed radical cyclization of N-(2-iodo-aryl) acrylamides for the synthesis of diverse oxindole scaffolds was reported by Chen, Teng and their coworkers in 2023. The reaction of N-(2-iodo-aryl) acrylamides 382 and vinyl arenes 383 in the presence of Pd(OAc)₂, DPEPhos and t-BuOLi in 1,4-dioxane under the irradiation of blue LEDs at room temperature for 20 h gave oxindole products 384 in good to excellent yields (Scheme 78) [102]. In the proposed reaction mechanism the visible light-excited [Pd⁰]^* reacts with 382 to provide aryl hybrid Pd-radical intermediates 385 which leads to the formation of alkyl hybrid Pd-radical species 386 and 386′ after 5-exo cyclization. The reaction of styrene 383 with 386′ to form 387 and 387′ followed by β-H elimination gives products 384.

Han and coworkers introduced a radical reaction of β,γ-unsaturated hydrazones for the synthesis of pyrazoline-functionalized oxindoles in 2015. The reaction of β,γ-unsaturated hydrazones 388 and N-aryl acrylamides 389 in the presence of DTBP (di-tert-butyl peroxide) under the solvent-free conditions at 100 °C for 72 h gave products 390 in good to excellent yields (Scheme 79) [103]. The t-BuO radical derived from DTBP abstracts H from β,γ-unsaturated hydrazones 388 to give radicals 391 followed by cyclization to form radicals 392. The addition of 392 to N-aryl acrylamides 389 form radicals 393 followed by the second cyclization and oxidative aromatization with DTBP yield pyrazoline-functionalized oxindoles 390. The same group extended the scope for the reaction of unsaturated ketoximes for the synthesis of isoxazoline-functionalized oxindoles and dihydroquinolinones. The reaction of unsaturated ketoximes 395 and N-arylpropiolamides or N-arylacrylamides 396 in the presence of TBHP at 100 °C for 24–48 h gave products 397 in good to excellent yields (Scheme 80) [104].

Han and coworkers reported a Cu-catalyzed reaction of unsaturated ketoximes for the synthesis of alkynylated isoxazolines and cyclic nitrones. The reaction of unsaturated ketoximes 398 and ethynylbenziodoxolones (EBX) 399 in the presence of Cu(OTf)₂ in DCE under Ar at 100 °C for 1 h gave products 400 in moderate to good yields (Scheme 81) [105]. In the reaction process, Cu^II catalysis converts ketoximes 398 to iminoxyl radicals which have resonance structures 401 and 402. Subsequent O-/N-atom 5-exo cyclizations of 401 and 402 yield radical intermediates 403 and 404, respectively. The addition of 403 or 404 at alkyne moiety of EBX 399 followed by the Cu^I-assisted elimination of 2-iodobenzoate gives products 400a or 400b.

An Ag-catalyzed radical reaction of unactivated olefins for the synthesis of substituted quinone was reported by Li and coworkers in 2022. The reaction of unactivated olefins 405 (such as N-aryl-4-pentenamides and N-aryl allyl carbamates) and quinones 406 in the presence of Ag₂O and K₂S₂O₈ in CH₃CN/H₂O at 100 °C for 10 h gave substituted quinone products 407 in good to excellent yields (Scheme 82) [106]. Amidyl radicals 408 generated via H-abstraction of N-aryl-4-pentenamides 405 by SO₄^•− radical undergo 5-exo cyclization to give radicals 409 which then add to menadiones 406 followed by an Ag^II-induced HAT to give products 407.

In 2023, Chen, Huang and their coworkers reported a photo-induced radical reaction of N-allyl-2-bromo-2,2-difluoroacetamides for the synthesis of α,α-difluoro-g- lactam-fused quinoxalin-2(1H)-ones and coumarins. The reaction of N-allyl-2-bromo- 2,2-difluoroacetamides 410 and quinoxalin-2(1H)-ones 411 or coumarins 411’ in the presence of PMDETA and LiOH in CH₃CN under the irradiation of 24 W blue LEDs for 36 h gave α,α-difluoro-g-lactam-fused quinoxalin-2(1H)-ones or coumarins 412 in moderate to excellent yields (Scheme 83) [107]. In this reaction process, PMDETA plays a dual role as an electron donor and hydrogen atom transfer reagent. The EDA (electron donor-acceptor) complexes 413 generated from 410 and PMDETA lead to the formation of difluoroalkyl radicals 414 after SET under the irradiation of blue LEDs. The 5-exo cyclization of radicals 414 followed by radical addition to quinoxalin-2(1H)-one 411 afford intermediates 415 which undergo H-abstraction with PMDETA^·+ to afford products 412.

5.2. O₂ as Y

Using molecular oxygen for the second functionalization could introduce a hydroxy or carbonyl group to the products. Han and coworkers in 2017 reported a Cu-catalyzed radical reaction of oxime-tethered alkynes for the synthesis of hydroxylated isoxazolines and dihydropyrrole oxides. The reaction of oxime-tethered alkynes 416 with O₂ in the presence of CuBr₂/toluene or Cu(OAc)₂/CH₃CN gave products 417 or 418 in good yields (Scheme 84) [108]. The proposed mechanism involves the generation of iminoxyl radicals, O-radical 419 and N-radical 420 resonance structures, via SET between Cu^II and oximes 416. Cyclization of 419 or 420 afford alkenyl radicals 421 or 422 followed by trapping of O₂ to yield the alkoxy radicals 423 or 424 after cyclization of peroxy radicals followed by the O−O bond cleavage. Products 417 and 419 are generated from the H abstraction of 423 and 424, respectively. A related reaction of unsaturated oximes for the synthesis of hydroxylated dihydropyrrole oxides was reported by Li’s group. The reaction of unsaturated oximes 425 and O₂ in the presence of CuBr/DMSO and DABSO (1,4-diazoniabicyclo[2.2.2]-octane-1,4-disulfinate) in EtOH at 50 °C for 12–24 h gave hydroxylated dihydropyrrole oxides 426 in good yields (Scheme 85) [109].

A visible-light-induced radical reaction of β,γ-unsaturated oximes for the synthesis of isoxazolines by Yu, Chen and coworkers in 2022. The reaction of β,γ-unsaturated oximes 427 using graphitic carbon nitride (g-C₃N₄) as photocatalyst in the presence of NaHCO₃ in CH₃CN/H₂O under the irradiation of 10 W blue LEDs for 36 h gave OH-decorated isoxazolines 428 in moderate to good yields (Scheme 86) [110]. In the reaction process, the photo irradiation of the semiconductor g-C₃N₄ generates an electron and a hole. Then, a single-electron oxidation of the hole in the valence band with water forms hydroxyl radical and proton, while in the conduction band, the single-electron reduction in the electron and the O₂ in air gives superoxide anion and water. The superoxide radical anion is protonated to produce H₂O₂ which then is converted to a HO radical. Intermediates 429 produced by the reaction of allyl oximes 427 with base undergo SET to the hole to generate radical intermediates 430 and then radicals 431 after cyclization. The coupling of HO radical and 431 gives final products 428.

A Cu-catalyzed reaction of 2-arylethynylanilines for the synthesis of substituted 2-hydroxy-2-indol-3-ones was reported by Wu, Chen and their coworkers in 2023. The reaction of 2-arylethynylanilines 432 and O₂ in the presence of Cu(OTf)₂, Zn(OTf)₂ and 6,6′-dimethyl-2,2′-bipyridine CH₃CN/HFIP (hexafluoro-iso-propanol) at 60 °C for 17–24 h afforded substituted 2-hydroxy-2-indol-3-ones 433 in good yields (Scheme 87) [111]. This reaction could be carried out at a gram-scale under the standard conditions to give product 433a in 69% yield. In the reaction process, the N-center radicals 434 generated via H-abstraction from 2-arylethynylanilines 432 undergo 5-endo cyclization followed by reaction with O₂ to form peroxic species 435 for radical cyclization and subsequential O–O bond cleavage to form radicals 436. H-abstraction of 436 from substrates 432 gives products 433 while radicals 434 are regenerated for the reaction cycle.

A radical reaction of unsaturated hydrazones/ketoximes for the synthesis of heterocyclic compounds such as pyridazin-4(1H)-ones or oxazin-4(1H)-ones was reported by Jiang and coworkers in 2023. The reaction of β,γ-unsaturated hydrazones 437a or ketoximes 437b and diazonium tetrafluoroborates in the presence of Et₃N and O₂ in DCE at −20 °C for 24 h gave pyridazin-4(1H)-ones 438a or oxazin-4(1H)-ones 438b in good to excellent yields (Scheme 88) [112]. In the synthesis of 438a, anionic intermediates generated from hydrazones 437a via deprotonation of NHTs with Et₃N are oxidized by O₂ to form N-centered radicals 439 followed by 6-endo cyclization and capture with O₂ to form peroxide radicals 440. Then, 1,4-HAT of 440 gives C-radicals followed by the cleavage of the O−O bond to give radicals 441 which are oxidized, followed by dehydration and then reaction with aryldiazonium species to give products 438a.

5.3. SO₂ from DABSO as Y

Similar to the molecular oxygen, SO₂ from DABSO could be used as a reactant for the second functionalization to introduce the sulfonyl group to the products. Ye and coworkers in 2023 developed a visible light-induced photocatalyst-free reaction of N-allylbromodifluoroacetamides for the synthesis of difluoroamidosulfonylated quinolones. The reaction of N-allylbromodifluoroacetamides 443, N-propargylamine 444 and DABSO under the irradiation of 40 W blue LEDs for 18 h in DMA at room temperature gave difluoroamidosulfonylated quinolines 445 in moderate to good yields (Scheme 89) [113]. In the reaction process, EDA complexes 446 generated from N-allylbromo- difluoroacetamides 443 and DABSO under SET afford difluoroalkyl radicals 447 for 5-exo cyclization followed by the reaction with SO₂ to give difluoroamidosulfonyl radicals 448 which then react with N-propargylamines 444 to form vinyl radicals 449 followed by radical cyclization and deprotonative aromatization to afford products 445.

In 2021, Weng and coworkers reported a photoredox-catalyzed reaction of unactivated olefins for the synthesis of SO₂F-attached 5-membered heterocyclic compounds. The reaction of unactivated olefins 450 such as N-phenyl pent-4-enamide, DABSO and N-fluorobenzenesulfonimide (NFSI) in the presence of [Ir(dF(CF₃)ppy)₂(bpy)]PF₆ and K₃PO₄ in CH₃CN under the irradiation of blue LEDs for 10 h gave products 451 in good to excellent yields (Scheme 90) [114]. Amidyl radicals 452 generated from N-phenyl pent-4-enamides 450 via SET with [Ir^III]^* undergo 5-exo cyclization followed by radical trapping with SO₂ of DABSO to give alkylsulfonyl radicals 453. These trap the fluorine atom from NFSI to give products 451 with concomitant generation of (PhSO₂)₂N radical 454 which is converted to (PhSO₂)₂NH by oxidation of [Ir^II] to [Ir^III]. Wang and coworkers reported a similar reaction of unsaturated hydrazones for the synthesis of SO₂F-functionalized pyrazolines. The reaction of β,γ-unsaturated hydrazones 455, DABSO and NFSI in the presence of 2,4,6-collidine, EtOH under Ar at 25 °C for 24 h gave products 456 in good to excellent yields (Scheme 91) [115]. Products 456 could be further transformed into sulfonate esters and amides.

5.4. Y from Other Neutral Molecules

Other than alkenes, molecular oxygen and SO₂ described above, isocyanides, imines, CO, and B₂(OH)₄ could be used for the second functionalization reactions. The Han group reported a radical reaction of β,γ-unsaturated ketoximes for the synthesis of isoxazoline-functionalized phenanthridines in 2014. The reaction of β,γ-unsaturated ketoximes 457 and 2-arylphenylisonitriles 458 in the presence of t-BuOOH and n-Bu₄NI in CH₃CN at 80 °C for 24 h gave products 459 in good yields (Scheme 92) [116]. In the reaction process, t-BuO radical and I₂ are produced by the reaction of t-BuOOH with n-Bu₄NI with concomitant H-abstraction of oxime 457 to yield iminoxyl radicals 460 for 5-exo cyclization to form radicals. Then, these are added to 2-isocyanobiaryl 458 to yield imidoyl radicals 461 that cyclize to the adjacent phenyl ring to form radicals 462 which undergo oxidative aromatization with I₂ or TBHP to afford products 459.

In 2018, Polyzos and coworkers reported a continuous-flow reaction of alkenyl-tethered arenediazonium salts for the synthesis of 2,3-dihydrobenzofurans. The flow reaction of alkenyl-tethered arenediazonium salts 463, CO and ROH in the presence of [Ir(dtbbpy)(ppy)₂]PF₆ in CH₃CN under the irradiation of blue LEDs gave products 464. The reaction can be completed in a short time of 200 seconds and is scalable (Scheme 93) [117]. In the reaction process, photo-exited catalyst PC^* promoted the reaction of diazonium tetrafluoroborates 463 to form radicals 465 which undergo 5-exo cyclization to yield radicals. The latter traps CO to give acyl radicals 466 which are oxidized with PC^•+ to 467 and then react with ROH and BF₄⁻ to afford products 464.

Studer and coworkers reported a radical reaction of unactivated alkenes for the synthesis of cyclic 1,2-aminoboronic esters. The reaction of unsaturated aryloxy-amides 468 or ketoximes 469 and B₂(OH)₄ under the irradiation of blue LEDs with DMA as a solvent gave cyclic boronic esters 470 or 471 in good yields (Scheme 94) [118]. The proposed mechanism suggested that EDA complexes 472 generated from the reaction of 468 and B₂(OH)₄ are converted to radicals 473 under the photo conditions and then undergo 5-exo cyclization to form radicals 474. The reactions of 474 with B₂(OH)₄ and then with DMA produce radicals 475 followed by the homolysis of weak B−B bond to give boronic acids 476 along with the DMA-stabilized B-centered radical 477. The reactions of boronic acids 476 with pinacol and Et₃N give cyclic boronic esters 470.

In 2023, Gong and Lu and coworkers reported a Fe-catalyzed radical reaction of unsaturated oxime esters for the synthesis of pyrroline-containing amino acid derivatives. The reaction of γ,δ-unsaturated oxime esters 478 and glycine derivatives 479 in the presence of Fe(OAc)₂ and 3,4,7,8-tetramethyl-1,10-phenanthroline in EtOAc/DMA at 78–80 °C for 5–7 h gave pyrroline-containing amino acids derivatives 480 in good to excellent yields (Scheme 95) [119]. The iminyl radicals 481 generated via the reductive cleavage of N–O bond of oxime ester 478 undergo 5-exo cyclization to give alkyl radicals 482 and then react with imines 483 generated from 479 to give N-centered radicals 484. Final products 480 are obtained via SET of Fe^IIL_n to radicals 484.

6. Second Functionalization with Other Forms of Y (Y^•+, Y⁺, and Y⁻)

In the cyclative radical difunctionalization reactions, the cyclized radicals could be converted to cations, anions or other reactive species for the second functionalization with the right counterparts. Presented in this section are the reactions using Y^•+, Y⁺ and Y⁻ for the second functionalization reactions (Scheme 96).

In 2022, Zhou, Sun and their coworkers reported a photo-promoted radical reaction of bromodifluoroacetamides with quinoxalin-2(1H)-ones for the synthesis of α,α-difluoro-γ-lactam-fused quinoxalin-2(1H)-ones (Scheme 97) [120]. The reaction of bromodifluoroacetamides 485, quinoxalin-2(1H)-ones, 4CzIPN, and DBU in EtOH and under the irradiation of blue LEDs for 24 h gave α,α-difluoro-γ-lactam-fused quinoxalin-2(1H)-ones 486 in moderate to good yields. In this reaction, excited-state 4CzIPN^* reacts with quinoxalin-

2(1H)-one to form radical cation 487 and 4CzIPN^–, and the latter reacts with bromodifluoroacetamides 485 to give difluoroalkyl radicals 488. Radicals 489 generated from 5-exo cyclization of radicals 488 are attacked by 487 to give intermediates 490 and then products 486 after deprotonation with a base.

He, Banwell and their coworkers, in 2023, introduced a visible light-mediated radical reaction of unsaturated oximes for the synthesis of methylene-bridged bis-heterocyclic compounds. The reaction of β,γ-unsaturated oximes 491, N-methoxy quinolinium salts 492, and Mn(OAc)₃·2H₂O with [Ir(dF(CF₃)ppy)₂(bpy)]PF₆ as a photocatalyst under the irradiation of blue LEDs for 16 h gave dihydroisoxazoline-attached pyridines or quinolone 493 in good to excellent yields (Scheme 98) [121]. In the reaction process, methoxy radical generated from pyridinium salts 492 abstract an H atom from oximes 491 to form O-centered iminoxyl radical 494 which then undergoes 5-exo cyclization to form radical 495. The reaction of radicals 495 and 492 gives radical cation 496 and then 497 after deprotonation. The demethylation via homolytic N–O bond cleavage affords oxazoline-attached quinolines 493 and regenerates the methoxy radical to complete the radical-chain process.

In 2014, Moeller and coworkers reported a radical reaction of O-benzyl hydroxamates or N-phenyl amides for the synthesis of five and six-membered lactams. In an electrolysis cell equipped with a reticulated vitreous carbon (RVC) anode and a platinum wire cathode, the reaction of electron-rich olefins such as O-benzyl hydroxamates or N-phenyl amides 498 in MeOH as a solution, Et₄NOTs as the electrolyte, and LiOMe as a base, lactam products were obtained 499 in good yields (Scheme 99) [122]. In the synthesis of 6-membered lactams, amidyl radicals 500 generated anodically from O-benzyl hydroxamates 498 undergo a 6-exo cyclization to give radicals 501 which are oxidized to cations 502 followed by MeOH trapping to give final products 499.

Tong and coworkers, in 2015, reported a Pd-catalyzed radical reaction of N-allyl-α-chloroamides for the synthesis of substituted γ-lactams. The reaction of N-allyl-α-chloroamides 503 in the presence of Pd(cod)Cl₂ catalyst, N-heterocyclic carbene ligand (IMes), NaI additive, and Cs₂CO₃ base in o-xylene at 135 °C gave β-iodomethyl γ-lactam 504 in moderate to good yields and good stereoselectivity (Scheme 100) [123]. The proposed reaction mechanism suggests that radicals 505 produced from chloroamides 503 undergo 5-exo cyclization followed by single-electron oxidation with Pd^IIL_n to give cations 506. Further reaction with NaI gives products 504.

An electrochemical dearomative spirocyclization reaction of N-acyl thiophene-2-sulfonamides for the synthesis of spirocycles was reported by Ye in 2022. The reaction of N-acyl thiophene-2-sulfonamides 507, n-Bu₄NOAc and HOAc in an undivided cell (carbon anode, Pt cathode) for 2.5 h gave spirocycles 508 in good yields (Scheme 101) [124]. It is a regio-specific radical spirocyclization of C2-tethered thiophenes. The complexes 509 produced from N-sulfonyl-benzamide 507 undergo electrochemical proton-coupled electron transfer (PCET) to yield amidyl radicals 510 which has a resonance structure of O-centered radicals 511. The 5-exo spirocyclization of radicals 511 followed by oxidation to thiocarbenium ions 512 and then nucleophilic interception yields spirocycles 508.

In 2023, Li and Fang and coworkers introduced a Cu-catalyzed radical reaction of N-aryl-4-pentenamides for the synthesis of cyano-substituted γ-lactams. The reaction of N-aryl-4-pentenamides 513, TMSCN, Cu(OAc)₂ and K₂S₂O₈ at 100 °C gave cyano-substituted γ-lactams 514 in moderate to good yields (Scheme 102) [125]. The proposed reaction mechanism suggested that amidyl radicals 515 generated from 513 via HAT with SO₄ radical anion undergo 5-exo cyclization followed by oxidization with Cu^II to give cations 516. Meanwhile, Cu^II is reproduced for the catalytic cycle with the aid of persulfate. Products 514 are obtained by the reaction of cations 516 and cyano anion.

An electrochemical reaction of N-propargylbenzamides for the synthesis of oxazole ketals was developed by the Xiao group in 2023. The reaction of N-propargylbenzamides 517 and n-Bu₄NPF₆ in an undivided cell with graphite rod anode and platinum plate cathode for 5 h produced oxazole ketals 518 in moderate to good yields (Scheme 103) [126]. In this reaction, anions generated from the deprotonation of 517 with MeO^– undergo anodic oxidation to give N-centered radicals 519 which have O-centered radicals 520 as the resonance structures. Cyclization of radicals 520 followed by anodic oxidation generates cations 521, which then react with MeO^– to form 522 and rearrange to compounds 523. Deprotonation of 523 with MeO⁻ followed by single-electron oxidation gives radicals 524 and then oxazole ketals 518 after anode oxidation and nucleophilic substitution with MeO^–.

7. Conclusions

In this article, radical difunctionalization reactions are presented. These reactions are initiated by radical cyclization followed by a second functionalization. It is a new addition to our previous reviews on radical 1,2-difunctionalization, remote 1,3-, 1,4-, 1,5-, 1,6- and 1,7-difunctionalization, and addition followed by cyclization difunctionalization reactions. For the current topic, the initial cyclization could result in a wide range of cyclic and heterocyclic compounds with variable ring size, while the second functionalization decorates the ring by atom transfer, radical or transition metal coupling, reacting with neutral molecules or with cationic and anionic species. There are many options for the second functionalization to increase the diversity of the products. Future work on the cyclative difunctionalization reactions could be directed to the development of new substrates for generating the initial radicals for cyclization. It is also important to develop new processes and reactants for the second functionalization. The recent advances in photoredox reactions, electrochemical reactions, and transition metal-catalyzed coupling reactions provide ample opportunities for both the formation of initial radicals and for the second radical functionalization. The synthetically efficient and operationally simple radical cyclative difunctionalization reactions can be further explored and fully utilized in the synthesis of unique compounds with potential biological and functional material applications.