Recent Advances in Iodine-Mediated Radical Reactions

Abstract

Over the past two decades, iodine-mediated free radical reactions have been extensively explored and employed in chemical transformations that complement traditional ionic reactions. In this review, we have updated the progress of the iodine-mediated radical reactions in organic synthesis reported between 2015 and mid-2024, and organized the reactions according to their mechanistic pathways. In general, the proposed mechanisms can be divided into four categories based on the radical initiation or its preceding steps, namely, (1) formation of a covalent X–I (X=C, N, S, Se) bond, which subsequently participates in a radical reaction; (2) formation of a noncovalent N···I bond, which assists the homolysis of the I–I bond; (3) formation of the key iodine radicals by visible-light or heat induced homolysis of I₂ or by electrochemical oxidation of iodide; (4) iodine induced peroxide decomposition via single electron transfer (SET) mechanism to generate alkoxy or alkyl peroxy radicals. We hope this review will provide readers with a comprehensive update on the iodine-mediated radical reactions, thereby further inspiring more exciting advances in this emerging field.

1. Introduction

Molecular iodine and iodide salts are environmentally friendly, readily available, and easy to handle materials. Over the past two decades, they have attracted great attention as a catalyst or promoter in the field of organic synthesis for various types of reactions such as oxidative cross-dehydrogenative coupling reactions,^[1] electrophilic cyclization reactions,^[2] iodination reactions,^[3] and multicomponent reactions.^[4]

The development of modern methods for generating free radicals under mild conditions has greatly advanced the field of synthetic organic chemistry and has led to the discovery of new reaction mechanisms for the synthesis of complex molecules that are difficult to access by the conventional ionic reaction pathways.^[5] In this regard, the iodine-mediated reactions involving free radical mechanisms have achieved great success to date.

Several excellent review articles had summarized the progress in the field from different perspectives prior to 2015.^[1a,b,4a,6] The rapid development of the field demands an up-to-date review of the iodine-mediated free radical reactions, especially to gain a deeper understanding of the complex mechanisms involved in these processes. While the previous reviews organized the material primarily according to the categories of chemical bond formation, our experience in studying the iodine-mediated chemistry showed that knowledge of the reaction mechanism was crucial for developing new chemical reactions in this field.

Therefore, we have organized this review article according to the mechanistic pathways of the reactions that occur in the radical initiation step or the steps that precede it. We herein summarize the recent progress in iodine-mediated free radical reactions in organic synthesis from 2015 to mid-2024 and organize the reactions with similar mechanisms in chronological order.

To our knowledge, most of the iodine-mediated radical reactions fall into the following four categories based on the initiation mechanism (Scheme 1). In the Type I reaction, iodine forms a covalent bond with a substrate to generate an X–I (X=C, N, S, Se) bond in the key intermediate, which then undergoes homolysis (Scheme 1, Eq. 1). In the Type II reaction, iodine forms a non-covalent bond with the nitrogen atom in the substrate to assist the homolysis of the I–I bond (Scheme 1, Eq. 2). In the Type III reaction, iodine molecules undergo visible-light or heat induced homolysis, or iodides undergo electrochemical oxidation, both of which generate iodine radicals (Scheme 1, Eq. 3). In the Type IV reaction, iodine catalysts induce the decomposition of peroxides via a single electron transfer (SET) pathway to generate alkoxy or alkyl peroxyl radicals, which then initiate further radical reactions (Scheme 1, Eq. 4).

Scheme 1.

Iodine-mediated four types of radical reactions.

2. Formation of an X–I Covalent Bond in the Key Intermediate

2.1. Formation of a C–I Covalent Bond in the Key Intermediate

The following section covers the iodine-mediated radical reactions involving the formation of a C–I covalent bond in the key intermediate. There are two general ways forming the C–I covalent bonds in situ: (i) iodination of a carbonyl α–C–H bond (Scheme 2, Eq. 5); (ii) iodine-mediated decomposition of diazo or azo compounds accompanied with the loss of N₂ (Scheme 2, Eq. 6).

Scheme 2.

Two general ways to form the C–I covalent bonds.

In 2015, Lei and co-workers developed an iodine-catalyzed oxidative coupling between 1,3-diketones 1 and thiophenols 2 for the synthesis of β-dicarbonyl thioethers 3 with di-tert-butyl peroxide ((t-BuO)₂) as the oxidant (Scheme 3).^[7] The reaction proceeded via a radical substitution instead of a traditional nucleophilic substitution pathway. The α-iodo 1,3-diketone 4 produced from iodine and 1,3-diketone was proposed as the key intermediate, which underwent a radical substitution with aryl sulfenyl radical to furnish the thioether product.

Scheme 3.

I₂-catalyzed C–H/S–H oxidative coupling.

In 2023, Hazra and co-workers reported an iodine-mediated oxidative coupling between methyl ketones 5 and sulfonyl hydrazides 6 employing tert-butyl hydroperoxide (t-BuOOH) as the oxidant (Scheme 4).^[8] The methyl ketone 5 first reacted with iodine generating an α-iodoketone 7, which then underwent radical substitution with the sulfonyl radical to afford the β-keto sulfones 8.

Scheme 4.

I₂-mediated oxidative coupling between methyl ketones and sulfonyl hydrazides.

In 2018, Batra and co-workers developed an iodine-mediated synthesis of hydrazones 11 from active methylene compounds 9 and arylhydrazine hydrochlorides 10 in a basic medium in aerobic conditions (Scheme 5).^[9] In the presence of iodine, the active methylene compound 9 was first converted to the 2-iodo-3-oxonitrile intermediate 12, which then underwent C–I bond homolysis to generate the radical intermediate 13. Subsequently, the aryldiazene cation radical 14, produced by the air-mediated oxidation of arylhydrazine hydrochlorides 10, coupled with 13 to give the azo compound 15. The latter underwent tautomerization to afford the hydrazone 11.

Scheme 5.

I₂-mediated diazenylation of active methylene compounds with arylhydrazine hydrochlorides.

In the same year, Li and co-workers reported an iodine-catalyzed synthesis of cyclopropanes 16, epoxides 17, and pyrroles 18 from olefins and α-diazo esters (Scheme 6).^[10] Initially, the α-diazo ester reacted with I₂ to generate a diiodide intermediate 19, which then reacted with a second equivalent of α-diazo ester to form the ionic pair intermediate 20, which generated the C-centered radical 21 at elevated temperature. Under Ar atmosphere, the addition of 21 to styrene led to the benzylic radical 22, which then underwent intramolecular cyclization via the release of iodine to afford cyclopropanes. If (E)-N-styrylacetamide was used instead of styrene, pyrroles formed via the cyclopropane ring-opening and subsequent ring-closing and dehydration. On the other hand, in an O₂ atmosphere, the intermediate 21 was first trapped by O₂ leading to a peroxide radical 23, which then reacted with styrene forming a benzylic radical 24. The latter underwent fragmentation to generate an epoxide, ethyl-2-oxoacetate, and iodine.

Scheme 6.

I₂-catalyzed synthesis of cyclopropanes, epoxides, and pyrroles from olefins and α-diazo esters.

Wan and co-workers reported a synthesis of primary oxamates and α-ketoamides 26 by the oxidative coupling between diazo ketones/esters 25 and NH₄I using t-BuOOH as the oxidant. They proposed two mechanistic pathways (Scheme 7).^[11] Initially, NH₄I reacted with t-BuOOH to produce I₂, NH₃·H₂O and t-BuO·. In path I, the diazo compound 25 reacted with I₂ to generate the α-diiodo ketone 27, which then underwent a nucleophilic substitution with NH₃ to give intermediate 28. The latter underwent C–I bond homolysis to produce the radical intermediate 29, which was oxidized to product 26 by t-BuOOH mediated Kornblum-DeLaMare rearrangement. In path II, intermediate 30 was generated by the insertion of an iodide into the diazo compound 25, which then underwent a nucleophilic substitution with NH₃ to afford the α-aminoketone 31. The t-BuO· abstracted an α-hydrogen from 31 to afford the intermediate 29 as well.

Scheme 7.

Oxidative coupling between diazo ketones/esters and NH₄I.

In 2023, Wu and co-workers developed a visible-light-induced iodine-mediated coupling between 2-diazo-1,1,1-trifluoroethane 32 and arylacetylenes, involving the formation of 1,1,1-trifluoro-2,2-diiodoethane (34) and light induced homolysis of 34 to a C-centered radical 35 (Scheme 8).^[12] The latter underwent radical addition to arylacetylene to afford a vinylic radical followed by homocoupling and deiodination resulting in bistrifluoromethylated 1,3,5-trienes 33. Three C=C bonds were generated in one pot with a high stereoselectivity (E/Z ratio up to > 20 : 1) by this strategy.

Scheme 8.

Visible-light-induced iodine-mediated coupling between 2-diazo-1,1,1-trifluoroethane and arylacetylenes.

In 2019, Tang and co-workers developed an iodine-mediated alkylsulfenylation of imidazopyridines 36 with elemental sulfur (S₈) and dialkyl azo compounds 37 (Scheme 9).^[13] The authors proposed that iodine inhibited the self-coupling of the cyanoalkyl radicals generated from the thermal decomposition of dialkyl azo compounds by forming an equilibrium between the former and the key intermediate 2-iodo-2-methylpropanenitrile (39). Subsequent transformation was proposed to proceed via two different pathways. In path I, the cyanoalkyl radical reacted with S₈ to form a cyanoalkyl sulfenyl radical 40, which underwent a radical substitution on imidazopyridine 36 a to afford vulcanized imidazopyridines 38 a. In path II, the cyanoalkyl radical reacted with S₈ and iodine leading to the sulfenyl iodide 41, which then underwent an electrophilic aromatic substitution on imidazopyridine 36 a to afford the product 38 a.

Scheme 9.

I₂-mediated alkylsulfenylation of imidazopyridines with dialkyl azo compounds and elemental sulfur.

2.2. Formation of an N–I Covalent Bond in the Key Intermediate

The reactions covered in the following section involve the oxidation of iodine/iodide, followed by the reaction with a nitrogen containing substrate to generate an N–I bond in the key intermediate. The homolysis of the N–I bond produces an N-centered radical species. The latter undergoes a series of chemical transformations resulting in the formation of N-containing organic compounds, especially N-heterocycles (Scheme 10).

Scheme 10.

Iodine-mediated synthesis of N-containing organic compounds involving the formation of an N–I covalent bond in the key intermediate.

In 2015, Muñiz’s group presented a selective Csp³–H amination constituting the first Hofmann–Löffler reaction employing a catalytic amount of iodine and one equivalent of oxidant (PhI(mCBA)₂), affording pyrrolidines (Scheme 11).^[14] The reaction accommodated a broad substrate scope including the primary, secondary, and tertiary, as well as both benzylic and nonbenzylic C–H bonds. The proposed mechanism showed that iodine was initially oxidized by PhI(mCBA)₂ to form I(mCBA), which reacted with the sulfonamide 42 a to generate an N–I bond in intermediate 44. The N–I bond then underwent visible-light-induced homolysis resulting in the N-centered radical 45. The latter underwent subsequent 1,5-hydrogen atom abstraction, iodination, oxidation, and intramolecular nucleophilic amination yielding the pyrrolidine product 43 a. Although the direct intramolecular nucleophilic amination of 46 yielding the pyrrolidine product appeared possible, the authors proposed the formation of the alkyl iodine(III) intermediate 47 instead, due to the better leaving group ability of the iodine(III) species.

Scheme 11.

I₂-catalyzed Hofmann–Löffler reaction.

Considering hypervalent organoiodine(III) reagents were less optimal from an economic and practical point of view, Muñiz and co-workers later reported that 2,4,6-triphenylpyrylium tetrafluoroborate (TPT) was an effective oxidant, cooperating with iodine in a catalytic amount to achieve an intramolecular benzylic C–H amination via visible-light irradiation (Eq. 7).^[15] The cyclization reaction was proposed to be light driven and significantly influenced by the ratio of I₂/TPT. Although the reaction (Eq. 7) took place under milder conditions than the former protocols (Scheme 11), it was limited to the benzylic C–H amination.

(Eq. 7)

Muñiz and co-workers subsequently reported a visible light induced Hofmann–Löffler reaction with a broader substrate scope employing a catalytic amount of I₂ and two equivalents of mCPBA (m-chloroperoxybenzoic acid), covering the amination of both the benzylic and nonbenzylic aliphatic C–H bonds (Eq. 8).^[16]

(Eq. 8)

Later, the same group reported an I₂/PhI(O₂CAr)₂ mediated direct Csp³–H fluorination with nucleophilic fluoride (NEt₃·3HF) (Scheme 12).^[17] The greater leaving group ability of the hypervalent organoiodine(III) intermediate 54 was proposed to enable the direct nucleophilic substitution with fluoride to generate the fluorination product 53 rather than the Hofmann–Löffler intramolecular cyclization product.

Scheme 12.

I₂-catalyzed Csp³–H fluorination with nucleophilic fluoride.

Nagib’s group also conducted a systematic investigation on the iodine-mediated Hofmann–Löffler reactions. In 2016, Nagib and co-workers developed a triiodide(I₃⁻)-mediated intramolecular δ-amination on unactivated secondary C–H bonds (Scheme 13).^[18] The authors proposed that the I⁻ was first oxidized to I₂ by PhI(OAc)₂ in situ, which further formed I₃⁻. The I₃⁻ species was detected by UV/Vis spectroscopy. This triiodide strategy attenuated the formation of transiently reactive acetyl hypoiodite (AcOI), which was prone to photoinitiated homolysis and therefore would lead to undesired oxidations of the α-aminyl C–H bonds, competing with the 1,5-hydrogen atom transfer (1,5-HAT) pathway for unactivated secondary C–H bonds.

Scheme 13.

I₃⁻-mediated intramolecular δ-amination on unactivated secondary C–H bonds.

Employing the triiodide-mediated C–H amination conditions, the same group developed the transformation from imidates 57 to oxazoline heterocycles 58, which were then subjected to HCl in MeOH or THF affording β-amino alcohols (Scheme 14).^[19] This streamlined protocol enabled rapid conversion of imidates to their β-amino analogues. The mechanistic studies indicated the 1,5-HAT was the rate-limiting step.

Scheme 14.

Iodine-mediated intramolecular C–H amination of imidates to oxazoline heterocycles and subsequent ring opening reactions.

Nagib’s group later developed a catalytic version of the I₂-mediated intramolecular C–H amination of imidates. The lower oxidant concentration of PhI(OAc)₂ accommodated a broader scope of functional groups, including alkenes, alkynes, and heteroarenes. The cholesterol analogue 59 was successfully synthesized by the method (Scheme 15).^[20]

Scheme 15.

I₂-catalyzed intramolecular C–H amination of imidates to oxazoline heterocycles and subsequent ring opening reactions.

In addition to the Muñiz and Nagib groups’ work, Bolm’s group also reported an iodine-mediated Hofmann–Löffler reaction of sulfoximines 60 affording dihydroisothiazole oxides 61 (Scheme 16). When the arylsulfoximine substrate bore an ortho-ethyl substituent, the two secondary benzylic C–H bonds displayed similar reactivity in the amination reaction and the corresponding dihydroisothiazole oxides were obtained in 46% and 44%, respectively.^[21]

Scheme 16.

I₂-mediated Hofmann–Löffler reaction of sulfoximines leading to dihydroisothiazole oxides.

In 2017, Sun and co-workers developed an iodine-catalyzed cascade azidation and cyclization of hydroxy/amino ethylene tethered indoles 62 with sodium azide, which led to C3-azidated furoindolines or pyrroloindolines 63 (Scheme 17).^[22] The proposed mechanism showed that the active intermediate was either N-chloro-N-iodobenzenesulfonamide (64) or ICl, which formed by the reaction of chloramine-B with iodine. Subsequently, these intermediates reacted with sodium azide to produce iodine azide 65, which underwent thermal homolysis to provide an azide radical. The latter reacted with tryptophol/tryptamine to provide the corresponding products.

Scheme 17.

I₂-catalyzed cascade azidation and cyclization to azidofuroindolines and -pyrroloindolines.

In 2019, Chattopadhyay and co-workers reported an iodine-mediated synthesis of 4-aryl-2-quinolone derivatives 67 via the intramolecular C–H amidation of 3,3-diarylacryl amides 66 (Eq. 9).^[23] The presence of the two aryl groups and the N-alkoxy substituent on the substrate was crucial to the success of the reaction.

(Eq. 9)

In 2024, Chupakhin and co-workers reported an I₂-catalyzed cross-dehydrogenative coupling between alicyclic amines 68 and 2H-imidazole oxides 69 (Scheme 18).^[24] A mechanistic study involving electron paramagnetic resonance spectroscopic experiments confirmed the radical pathway of the reaction. The formation of the N-centered radical 71 via the N–I bond homolysis was proposed to be stimulated by the Lewis base 2-MeTHF.^[25]

Scheme 18.

I₂-catalyzed cross-dehydrogenative coupling between 2H-imidazole oxides and alicyclic amines.

2.3. Formation of an S/Se–I Covalent Bond in the Key Intermediate

The following section describes the reactions between iodine and sulfur/selenium reagents to form an intermediate containing an S/Se–I covalent bond, followed by homolysis of the S/Se–I bond to form an S/Se-centered radical intermediate, which leads to an S/Se-containing organic compound in subsequent transformations (Scheme 19).

Scheme 19.

I₂-catalyzed synthesis of S/Se-containing organic compounds involving the formation of an S/Se–I covalent bond in the key intermediates.

In 2015, Yi and co-workers developed an iodine-mediated one-pot reaction for the difunctionalization of alkynes into β-iodoalkenyl sulfides 72 with high stereoselectivity (E/Z ratio up to 99/1) (Scheme 20).^[26] The proposed mechanism showed that sodium arylsulfinate was first reduced by I₂–PPh₃ forming the S–I bond in the key intermediate, arylsulfenyl iodide 73, which then underwent a homolysis to produce an aryl sulfenyl radical 74. Addition of 74 to alkyne or 1,2-diiodo alkene 75 led to the corresponding alkenyl radical 76 or alkyl radical 77, respectively. Subsequent radical substitution between 76 and 73 or elimination of iodine from 77 led to the β-iodoalkenyl sulfides 72 and the aryl sulfenyl radical 74.

Scheme 20.

I₂-mediated one-pot reaction for the synthesis of β-iodoalkenyl sulfides.

Liu and co-workers subsequently reported an iodine-promoted coupling reaction between alkynes and sodium sulfinates but in the absence of PPh₃. The reaction afforded (E)-β-iodoalkenyl sulfones 78 instead of (E)-β-iodoalkenyl sulfides (Eq. 10).^[27] The proposed mechanism indicated that molecular iodine played a dual role as both a radical initiator and the iodine source. The high stereoselectivity observed in favour of the E-isomer was attributed to the steric repulsion between the iodine and the sulfonyl group.

(Eq. 10)

In 2023, Kumar and co-workers reported an iodine-mediated three-component reaction of terminal alkynes, sodium sulfinates, and 1,3-diketones 79 to afford (Z)-β-oxyvinyl sulfones 80 (Eq. 11).^[28] When either quinoxalin-2(1H)-ones 81 or quinazolin-4(3H)-ones 82 were employed instead of 1,3-diketones, (Z)-β-amidovinyl sulfones were obtained in up to 88% yields (Eq. 12).

In addition to alkynes, alkenes were also employed in the iodine-mediated coupling reactions with sodium sulfinates. In 2015, Wang and co-workers described an iodine-mediated synthesis of vinyl sulfones 83 from sodium aryl sulfinates and alkenes in an aqueous medium (Scheme 21).^[29] Notably, when sodium methanesulfinate was employed instead of the arylsulfinate, β-iodo sulfones 84 were obtained in good yields, and no vinyl sulfones were observed. It was possibly due to the lower acidity of the 2-H in intermediate 88 when methanesulfinate was employed, which disfavoured the iodide mediated E2-elimination.

Scheme 21.

I₂-mediated synthesis of vinyl sulfones and β-iodo sulfones.

Yuan and co-workers prepared (E)-vinyl sulfones 90 by an I₂-mediated decarboxylative cross-coupling between cinnamic acid 89 and sodium sulfinate (Eq. 13).^[30] The base (K₂CO₃) presumably accelerated the decarboxylation.

(Eq. 13)

Later, Yadav and co-workers reported an I₂-mediated oxidative coupling of enol acetates 91 with sodium sulfinates resulting in β-keto sulfones 92 (Eq. 14).^[31] It’s worth noting that the R¹ group was limited to an aryl group, possibly because in the case of aliphatic enol acetates far less stable alkyl radicals would form after the addition of the sulfonyl radical to the aliphatic enol acetates as compared to the benzylic radicals formed in the case of the aromatic enol acetates.

(Eq. 14)

In 2015, Zhang and co-workers reported a stereospecific synthesis of E-vinyl sulfides by a copper and iodine co-mediated vinylic C–H oxidative sulfenylation (Scheme 22).^[32] The proposed mechanism suggested that aryl disulfides 93 first reacted with I₂ to afford ArSI, which then underwent thermal homolysis to generate an aryl sulfenyl radical. The latter underwent a radical addition to an olefin resulting in intermediate 95. Subsequent oxidation by I₂ and Cu(OTf)₂ led to the E-vinyl sulfides 94.

Scheme 22.

I₂ and Cu(OTf)₂ co-mediated synthesis of E-vinyl sulfides from terminal alkenes and diaryl disulfides.

Shao and co-workers subsequently reported an iodine-mediated sulfonylation of imidazopyridines 96 with sodium sulfinates (Eq. 15).^[33] It’s worth noting that in the presence of 2.0 equivalents of PPh₃, sulfides 98 were obtained instead of sulfones 97 (Eq. 16).

In addition to alkynes and alkenes, amines were also found to react with sodium sulfinates in the presence of I₂ leading to sulfonamides and sulfenamides. In 2015, Yuan and co-workers reported an I₂-mediated synthesis of sulfonamides 99 (Scheme 23).^[34] The proposed mechanism showed that sodium arylsulfinate initially reacted with iodine to generate sulfonyl iodide intermediate 100. Subsequently, a sulfonyl radical 101 was produced via the homolysis of the S–I bond, which then coupled with the amine affording the sulfonamide.

Scheme 23.

Synthesis of sulfonamides by I₂-mediated coupling of sodium sulfinates with amines.

In the same year, Yotphan and co-workers reported a similar method for the synthesis of sulfonamides 99 using a catalytic amount of iodine by adding two equivalents of sodium percarbonate (Eq. 17).^[35] The latter oxidized the in situ generated HI to I₂.

(Eq. 17)

Dong and co-workers recently developed iodine-catalyzed syntheses of sulfonamides 99 and sulfenamides 102 from sodium sulfinates and amines (Eq. 18).^[36] In the presence of the strong oxidant K₂S₂O₈, various sulfonamides were obtained in up to 94% yields within 6 h. On the other hand, when PPh₃ was employed, sulfenamides were synthesized within a shorter reaction time.

(Eq. 18)

Although sodium sulfinate is the most common sulfonylation reagent employed in synthesizing S-containing organic compounds, triethylammonium thiolates, sulfonyl hydrazides, p-toluenesulfonylmethyl isocyanide (TosMIC), thiophenols, 1-aryltriazene/CS₂, and disulfides are also known sulfur reagents employed in the I₂-mediated radical coupling reactions.

In 2016, Li and co-workers developed an I₂-catalyzed formal [3 + 2] annulation between triethylammonium thiolates 103 and arylhydrazines in oxygen atmosphere, leading to 1,2,3-thiadiazoles 104 (Scheme 24).^[37] The proposed mechanism involved a hydrazone formation between the ketone group in the thiolate substrate and aryl hydrazine, formation of an sulfenyl iodide intermediate, and homolysis of the S–I bond forming the sulfenyl radical, followed by an intramolecular radical coupling-cyclization and SET processes.

Scheme 24.

I₂-catalyzed formal [3 + 2] annulation between triethylammonium thiolates and arylhydrazines.

In 2017, Yallapragada’s group reported an iodine-mediated sulfonylation of olefins and alkynes employing p-toluenesulfonylmethyl isocyanide (TosMIC) 105 as the sulfonylating agent, providing a variety of vinyl, allyl, and β-iodo vinyl sulfones (Scheme 25).^[38]

Scheme 25.

I₂-mediated synthesis of vinyl sulfones employing TosMIC as a sulfonylating agent.

In 2018, Gong and co-workers developed an iodine-promoted iodosulfonylation reaction of alkynes with sulfonyl hydrazides in an aqueous medium (Eq. 19).^[39] A range of β-iodo vinylsulfones 106 were prepared with excellent E selectivity.

(Eq. 19)

In 2022, Wan and co-workers reported a KI-catalyzed sulfenylation reaction of unprotected 8-aminoquinolines 107 with sulfonyl hydrazides in air (Eq. 20).^[40] The reaction displayed interesting solvent effects. In p-xylene, 5-sufenylated 8-aminoquinolines 108 were obtained. While, 5,7-disulfenylated 8-aminoquinlines 109 were generated in toluene.

(Eq. 20)

In 2019, Lei and co-workers developed an I₂-catalyzed thiolation/selenation and oxidation of 1,2,3,4-tetrahydroisoquinolines 110 with thiols and selenols in an O₂ atmosphere, leading to various 4-sulfenylisoquinolines and 4-selenylisoquinolines (Scheme 26).^[41] The proposed mechanism showed that I₂ first oxidized the thiols/selenols to sulfenyl/selenyl iodides via the disulfide/diselenide intermediates. Subsequent coupling between 1,2,3,4-tetrahydroisoquinolines 110 and sulfenyl/selenyl iodides affording the 2-(sulfenyl/selenyl)-1,2,3,4-tetrahydroisoquinoline intermediates 111. Iodine-mediated oxidation of 111 led to the isoquinolinium salt 112. Rearrangement of the sulfenyl/selenyl group on the isoquinoline framework led to the 4-sulfenyl/selenyl isoquinolines.

Scheme 26.

I₂-catalyzed thiolation/selenation at the C4-position of 1,2,3,4-tetrahydroisoquinolines.

In 2020, Singh and co-workers developed an I₂-catalyzed synthesis of 3-arylthioindoles, employing a blend of 1-aryltriazene/CS₂ as the aryl sulfenyl source (Scheme 27).^[42] The proposed mechanism showed that I₂ first assisted the decomposition of (E)-1-(aryldiazenyl)pyrrolidine 113 forming diazonium ion 114, N-iodopyrrolidine, and iodide. 114 was then reduced by iodide to an aryl radical, which underwent a radical addition to carbon disulfide forming the radical intermediate 115. Subsequent loss of carbon monosulfide led to an aryl sulfenyl radical 116, which underwent radical substitution on the indole ring.

Scheme 27.

I₂-catalyzed synthesis of 3-arylthioindoles.

In 2021, Chatterjee and co-workers reported an oxidative sulfenylation and annulation of 2-alkynyl biaryl compounds 117 with disulfides and synthesized 9-sulfenylphenanthrenes and related polycyclic heteroarenes 118 in an aqueous medium (Eq. 21).^[43] An in situ formation of arylsulfenyl iodide from diaryl disulfide and I₂ was proposed. The same group later synthesized a variety of selanyl polycyclic aromatic hydrocarbons (PAHs) and polycyclic heteroarenes 119 employing a similar protocol via the in situ formation of the corresponding selenyl iodide intermediates (Eq. 22).^[44]

In 2023, the same group reported a synthesis of trisubstituted vinyl sulfides and selenides 120 from 1,1-diarylethenes and disulfides/diselenides under similar reaction conditions (Scheme 28).^[45] They mainly investigated the reaction between symmetrical 1,1-diarylethenes and disulfides/diselenides. When unsymmetrical 1,1-diarylethene 121 was subjected to the reaction with 1,2-diphenyldisulfide/1,2-diphenyldiselenide, the corresponding products were obtained with poor stereoselectivity, and the Z/E ratio was nearly 1 : 1. On the other hand, an unsymmetrical 1,1-diarylethene 122 bearing two aryl groups with a greater steric hindrance difference afforded the E-isomer as the sole product.

Scheme 28.

Synthesis of vinyl sulfides and selenides by I₂-catalyzed oxidative chalcogenation of 1,1-diarylethenes.

Zeng and co-workers developed a KI/K₂S₂O₈-mediated regioselective 1,2-thio(seleno)amination of alkenes with NH₄SCN and disulfides/diselenides in an aqueous medium (Scheme 29).^[46] The proposed mechanism showed that K₂S₂O₈ first underwent homolysis to generate a sulfate radical anion (SO₄^•−), which oxidized I⁻ to I₂. Subsequent reaction between I₂ and diselenide led to the formation of aryl selenyl iodide, which reacted with alkenes resulting in the benzylic radical 123. Meanwhile, SCN⁻ was oxidized by SO₄^•− to isothiocyanate radical. The cross radical coupling between the latter and 123 led to the final addition product.

Scheme 29.

. Isothiocyanochalcogenation of alkenes with NH₄SCN and disulfides/diselenides.

The same group subsequently reported a blue light-induced n-Bu₄NI/K₂S₂O₈ mediated 1,2-selenoamination of alkenes (Eq. 23).^[47] The aryl selenenyl iodide (ArSe–I) generated in situ from diaryldiselenide and iodine was proposed to undergo blue-light induced homolysis, leading to the key aryl selenyl radicals.

(Eq. 23)

Liu’s group recently developed an iodine-catalyzed 1,2-thio(seleno)amination of alkenes with 1-(methylsulfonyl)-1,2,3-triazoles and disulfides/diselenides via a tandem radical coupling process in air (Scheme 30).^[48] The mechanism study indicated that the formation of the C–N bond proceeded via a desulfonation-associated radical cross-coupling process, leading to a pair of regioisomers 124 and 125 favouring the N2-alkylation products on the 1,2,3-triazole ring (124).

Scheme 30.

I₂-catalyzed radical coupling of alkenes with 1,2,3-triazoles and disulfides/diselenides for 1,2-thio/seleno amination.

Liang and co-workers recently reported an iodine-mediated tandem dehydrogenation and regioselective dichalcogenation of indolines 126 (Scheme 31).^[49] In the presence of 30 mol% of I₂ and 2.0 equivalents of DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone, Condition A), the indolines first underwent dehydrogenation to afford indoles, which then underwent sequential coupling with sulfenyl/selenenyl iodide at the C3 and C2 positions. On the other hand, in the presence of 1.0 equivalent of I₂, the indolines first underwent coupling with sulfenyl/selenenyl iodide at the C5 position followed by dehydrogenation and further coupling with sulfenyl/selenenyl iodide at the C3 position. I₂ was proposed to be the catalyst of the oxidative dehydrogenation as well as the reagent responsible for the generation of the ArS–I/ArSe–I species.

Scheme 31.

I₂-mediated tandem dehydrogenation and regioselective dichalcogenation of indolines.

In 2023, Wang and co-workers reported a visible-light-induced iodine-catalyzed synthesis of unsymmetrical disulfides 127 (Scheme 32).^[50] The proposed mechanism showed that the key intermediate R¹S–I was first generated by the reaction between iodine and thiophenol. The sulfenyl radical intermediate 128 was subsequently produced by the visible-light-induced homolysis of the S–I bond. On the other hand, the other sulfenyl radical 129 was generated by an iodine radical-mediated hydrogen-abstraction. The disulfide product 127 was formed by a cross radical coupling reaction. The reason for the higher selectivity observed for the cross-coupling than the self-coupling remains to be further elucidated.

Scheme 32.

Visible-light-induced I₂-catalyzed synthesis of unsymmetrical disulfides.

3. N···I Noncovalent Bond Induced Radical Reaction

In 2016, Xi and co-workers reported a halogen-bond-assisted iodine-mediated benzylic C–H functionalization of di-ortho-substituted azobenzenes 130 (Scheme 33).^[51] Molecular iodine served as both a radical initiator and an oxidant in the reaction, affording 2H-indazoles 131. It’s worth noting that mono-ortho-substituted azobenzenes were unreactive in the reaction. The proposed mechanism showed that the nitrogen atom in the azo substrate 130 first coordinated with I₂, to form a noncovalent halogen bond N···I (132). The radical chain reaction started via the halogen-bond assisted homolysis of the I–I bond to afford a bound radical intermediate 133. Subsequently, the bound iodine radical assisted hydrogen atom transfer from the benzylic position to the azo group led to the N-centered radical 134, which then underwent an intramolecular nucleophilic substitution to afford the cyclization intermediate 135. The latter was converted to a more stable intermediate 136 via proton transfer. Finally, abstraction of the second benzylic hydrogen by I₂ furnished the protonated product 137 and concomitantly regenerated an iodine radical.

Scheme 33.

I₂-mediated 2H-indazole synthesis via halogen bond-assisted benzylic C–H functionalization.

The same group subsequently developed a protocol employing a catalytic amount of I₂ under O₂ atmosphere fulfilling the same conversion from ortho-alkylazobenzenes 130 to 2H-indazoles 131 in comparable yields (Eq. 24).^[52] CuI was found to be an effective additive to accelerate the regeneration of iodine in the catalytic cycle. Consistent with their former work, substrates bearing only one ortho-alkyl group were unreactive.

(Eq. 24)

In 2019, Sekar and co-workers reported a halogen bond-assisted electron-catalyzed iodination of isoquinoline 138, quinoline 139, and 1H-pyrrolo[2,3-b]pyridine derivatives 140, employing substoichiometric amounts of I₂ and t-BuOOH (Eq. 25).^[53] The authors proposed the formation of the halogen bond between the heteroarene substrates and I₂ not only enhanced the single electron transfer process, but also stopped the undesirable Bray–Liebhafsky reaction and thus reduced the loading of t-BuOOH.

(Eq. 25)

4. Iodine Radical as the Key Active Species

In the reactions discussed in the following section, iodine radical is proposed to be the key active species. In general, there are three common strategies to generate the iodine radicals: (1) thermal homolysis of I₂; (2) visible-light-induced homolysis of I₂; and (3) anode oxidation of I⁻.

4.1. Iodine Radical Produced by Thermal Homolysis of I₂

In 2015, Li and co-workers developed an NH₄-I-mediated oxysulfenylation of styrenes, with DMSO and alcohols.^[54] β-Alkoxy methyl sulfides 141 were obtained in excellent regioselectivity. The proposed mechanism showed that iodine radical and CH₃SH were first generated (Scheme 34), which reacted with each other leading to a methylthiyl radical (CH₃S•). Addition of the latter to styrene resulted in a benzylic radical intermediate 142. Concurrently, iodine radical abstracted a hydrogen from the alcohol to afford an alkoxy radical (RO•). Addition of the latter to 142 leads to the product.

Scheme 34.

NH₄I-mediated oxysulfenylation reaction of styrenes with DMSO and alcohols.

In 2016, Wan’s group reported an n-Bu₄NI-catalyzed synthesis of β-carbonyl sulfones 144 by the coupling of sulfonyl hydrazides with α-keto diazo compounds 143 (Scheme 35).^[55] The proposed mechanism showed that iodide was first oxidized to I₂ in air. The latter underwent thermal homolysis to generate iodine radicals, which mediated the denitrogenation of sulfonyl hydrazide leading to the sulfonyl radical 145. Subsequently, the carbene (146), generated from the thermal decomposition of the diazo compound, coupled with 145 affording the radical intermediate 147, which abstracted a hydrogen forming the final product.

Scheme 35.

n-Bu₄NI-catalyzed cross-coupling between sulfonyl hydrazides and diazo compounds.

In 2020, Liang and co-workers reported an I₂-catalyzed three-component reaction of naphthalen-2-amine 148, aldehydes, and selenium powder, leading to 2-phenylnaphtho[2,1-d]selenazoles 149 (Eq. 26).^[56] Naphthalen-1-amines also reacted with aldehydes and selenium powder under the same reaction conditions, affording naphtho[1,2-d][1,3]selenazoles in medium yields.

(Eq. 26)

In 2022, Baruah’s group developed an iodine-catalyzed synthesis of 1,4-enediones 151 from styrenes and sulfoxides 150 in air (Eq. 27).^[57] The products were obtained in high yields as a mixture of E and Z stereoisomers with the former as the major isomer. Both of the carbonyl oxygen atoms in the products were proposed to originate from air.

(Eq. 27)

In 2023, Tu and co-workers reported an iodine-mediated cyclization of o-vinylaryl isocyanides 152 and subsequent halogenation with disulfides/diselenides, providing a regioselective protocol for the synthesis of 2-chalcogenated quinolines 153 (Scheme 36).^[58] The proposed mechanism showed that the homolysis of molecular iodine at elevated temperature first generated iodine radicals. The imidoyl radical intermediate 154 generated from the addition of iodine radical to o-vinylaryl isocyanides 152a underwent subsequent intramolecular cyclization, iodine radical addition, and hydroiodide elimination to produce the heteroaryl iodide 155. The phenylthiyl radical generated from the homolysis of diaryl disulfide then substituted the iodo group to afford 2-chalcogenated quinolines.

Scheme 36.

I₂-mediated radical cyclization of o-vinylaryl isocyanides and subsequent halogenation with disulfides/diselenides.

In 2021, the Xu and Xia’s group developed a sequential organo/iodine binary catalytic protocol for the one-pot synthesis of C₂-symmetric axially chiral 1,4-dicarbonyl compounds 158 with 2,3-quaternary stereocenters (Scheme 37).^[59] In the organocatalytic cycle, the Michael addition product 160 was generated by the Re-face attack of the deprotonated 157 a to the organocatalyst-activated 156 a. In the I₂ catalytic cycle, the iodine radical was generated by the reaction between hydrogen iodide and H₂O₂. The iodine radical abstracted a hydrogen from 160 to afford the tertiary carbon radical intermediate 161. The homocoupling of 161 generated the product.

Scheme 37.

One-pot organo/iodine binary catalysis in the synthesis of C₂-symmetric axially chiral 1,4-dicarbonyl derivatives.

Employing a similar strategy shown in Scheme 37, the same group developed a one-pot reaction of amides with pyrazole-based primary amines in 2024 (Scheme 38).^[60] The reaction first involved an asymmetric organocatalytic Michael addition between nitroolefin 162 and pyrazolone 163 to generate adduct 167. Meanwhile, pyrazole-based primary amine 164, underwent an electrophilic aromatic substitution reaction with molecular iodine to quickly generate an iodinated intermediate 168. Finally, intermediates 167 and 168 undergo an iodine-mediated C(sp³)–N cross-coupling to afford the product 165.

Scheme 38.

Combining organocatalysis and I₂ catalysis in the synthesis of chiral α-amino amides with a quaternary stereocenter.

4.2. Iodine Radical Generated by Visible-Light-Induced Homolysis of I₂

Visible-light-induced photo-redox reactions have attracted enormous attention of chemists.^[61] The visible-light-induced radical reactions have been also explored in the iodine catalysis field. For example, the reactions described in Schemes 5, 8, 11, 13, 16, and 32, visible-light-induced homolysis of the C–I, S–I and N–I bonds. A compact fluorescent light (CFL) is employed as a common source of visible-light. In the following section, the reactions involving visible-light-induced homolysis of I₂ in the radical initiation step will be discussed.

Itoh’s group has conducted systematic research work in the field of visible-light-induced iodine-mediated synthesis of γ-lactones. In 2017 their group reported an iodine-mediated intermolecular tandem addition and esterification between alkenes and malonates 169 under visible-light irradiation (Scheme 39).^[5b,62] The method showed that the diastereoselectivity of the γ-lactone products were controlled by the choice of base, and Ca(OH)₂ turned out to be the best, favouring the cis-γ-lactones. The control experiments indicated that visible-light promoted the generation of iodine radicals by the homolysis of I₂. The proposed mechanism showed that the iodine radical first added to styrene yielding the vic-diiodoalkanes 170. In the presence of Ca(OH)₂, intermediate 170 underwent a nucleophilic substitution with malonate 169 a at the primary alkyl iodide bond, affording intermediate 171. Finally, an intramolecular cyclization led to the γ-lactones.

Scheme 39.

I₂-mediated tandem synthesis of γ-lactones from alkenes and malonates.

The Itoh group subsequently developed a visible-light-induced iodine-mediated intermolecular spirolactonization of alkenes with β-keto esters 172 (Eq. 28).^[63] The reaction took place via a similar mechanistic pathway to the one displayed in Scheme 39, with a slight preference for the cis-isomer in most cases. The control experiments suggested that the addition of water was crucial to the product formation. When malonates 173 were employed instead of β-keto esters, the reaion favoured the trans isomers of the γ-lactones (Eq. 29).^[64]

In addition to monoalkenes, conjugated dienes such as 1,3-dienes 174 were also applied to the iodine-mediated lactonization with malonates 175 under visible-light irradiation by Itoh’s group (Eq. 30).^[65] The γ-lactones were prepared regio-specifically in moderate yields and diastereoselectivities.

(Eq. 30)

The study of Itoh’s group on the visible-light-induced iodine-mediated synthesis of γ-lactones showed that the diastereoselectivity was determined during the cyclization step and was improved by the increased steric hindrance around the carbonyl moiety of the malonate substrates. Therefore, when Meldrum’s acid derivatives 176 were used as the substrates instead of malonate esters, a higher cis-diastereoselectivity in this lactonization reaction was achieved (dr = 90 : 10 vs. dr = 67 : 33) (Eq. 31).^[66]

(Eq. 31)

4.3. Iodine Radical Generated by Anode Oxidation of I⁻

In 2018, Lei’s group comprehensively reviewed the progress of iodine-catalyzed electrochemical oxidative coupling reactions.^[67] In 2020, the C–H functionalization via electrochemistry with various iodine-containing reagents was reviewed by Wang’s group.^[68] In this section, we have summarized the iodine-mediated electrochemical reactions reported after 2020.

In 2021, Zhang and co-workers developed an electrochemical protocol for alkyne difunctionalization. A wide scope of (E)-β-iodovinyl sulfones were prepared with excellent regio- and stereoselectivity (Eq. 32).^[69] Nitrogen and hydrogen gas were the byproducts. The proposed mechanism showed that iodides were first oxidized to iodine radicals on the anode, which then induced the denitrogenation of the aryl sulfonylhydrazide forming the aryl sulfonyl radical. Addition of the latter to alkyne followed by coupling with iodine radical resulted in the product.

(Eq. 32)

As part of their continuing interest in organic electrochemistry, the same group later reported a KI-catalyzed electrochemical synthesis of allylic sulfones 178 from α-methylstyrenes 177 and sulfonylhydrazides with an excellent regioselectivity (Scheme 40).^[70] The proposed mechanism showed that the anodic oxidation of iodide produced iodine radical, which reacted with arylsulfonyl hydrazide generating the arylsulfonyl radical 179 along with the loss of N₂. Subsequently, the benzylic radical 180, generated by the addition of an arylsulfonyl radical 179 to α-methylstyrene 177 a, was further oxidized by the iodine radical to afford the allylic sulfone product. A cathodic reduction of protons fulfilled the electrochemical cycle.

Scheme 40.

KI-catalyzed electrochemical allylic sulfonylation reaction.

In 2023, Cao and co-workers reported an electrochemical phenyl-carbonyl coupling reaction of aromatic aldehydes/ketones 181 (Scheme 41).^[71] With a carbon rod as the anode and a platinum plate as the cathode, the self-coupling reaction afforded 4-(hydroxy(phenyl)methyl)benzaldehydes/acetophenones 187. The proposed mechanism showed that the carbonyl group of benzaldehyde 181 a was first reduced to the radical anion 182 on the platinum cathode. The radical anion resonance structure 183 then coupled with another molecule of benzaldehyde to afford radical anion 184. The 1,3-hydrogen migration led to a new radical anion 185. Finally, the radical anion resonance structure 186 underwent an iodine radical mediated oxidation to afford the self-coupling product 187 a.

Scheme 41.

NH₄I-catalyzed self-coupling of aromatic aldehydes/ketones.

He and co-workers reported an electrochemical synthesis of β-haloesters 188 via 1,2-haloesterization of olefins with carboxylic acids and n-Bu₄NX (X=I, Br, and Cl) (Eq. 33).^[72] The reaction displayed high regio-selectivity and good functional group tolerance. n-Bu₄NX served as both the electrolyte and the halogen source.

(Eq. 33)

Göttlich and co-workers reported an electrochemical cyclization and chlorination of N-pentenylamines 189 and their hydrochloric acid salts 190 with n-Bu₄NI as a redox catalyst (Eqs. 34–35).^[73] By the electroorganic synthetic protocol, a variety of 3-chloropiperidine derivatives 191 were prepared with carbon rod as the anode and nickel rod as the cathode. The chloride source was proposed to be CH₂Cl₂ and HCl, respectively.

(Eq. 34)

(Eq. 35)

Yuan and Zhang developed an NH₄I-promoted electrosynthesis of 2-aminothiazoles 192 from ketones and NH₄SCN (Eq. 36).^[74] The iodide was proposed as the source of the iodine radical, which functioned as a radical initiator in the electrochemical cyclization. NH₄⁺ was the source of the amino group in the products. The addition of a base was critical, which neutralized the HI acid generated in situ.

(Eq. 36)

Bera and co-workers described an electrochemical synthesis of 1,2,3-triazoles 194 from propargyl alcohols 193 and sodium azide (Eq. 37).^[75] With the pencil graphite (PG) anode and stainless-steel cathode in CH₃CN, the azide-alkyne click reaction afforded the triazole products in moderate to good yields. The supporting electrolyte n-Bu₄NI played a dual role since the anodic oxidation of propargyl alcohol to ynone was mediated by the iodine radicals generated in situ.

(Eq. 37)

5. Iodine as a Radical Initiator to Decompose Peroxides

In the reactions discussed in the following section, iodine acts as a radical initiator to decompose peroxides via a single electron transfer (SET) mechanism to generate the key intermediates alkoxy or alkylperoxy radicals.

In 2015, Wang and co-workers reported an I₂-mediated iodosulfonylation reaction between alkenes and sulfonyl hydrazides in the presence of t-BuOOH (Scheme 42).^[76] The catalytic cycle of I₂/t-BuOOH promoted the decomposition of t-BuOOH to produce tert-butylperoxy radicals which then reacted with sulfonyl hydrazide by stepwise hydrogen abstractions followed by denitrogenation to afford the sulfonyl radical 195. A benzylic radical 196 formed via the radical addition of 195 to styrene. Finally, the reaction between 196 and I₂ provided β-iodosulfone.

Scheme 42.

I₂-mediated iodosulfonylation reaction between alkenes and sulfonyl hydrazides.

In 2019, Li and co-workers reported an iodine-mediated synthesis of sulfonylmethyl piperidines, pyrrolidines, and pyrazolines via aminosulfonylation of olefin-tethered sulfonamides with sulfonyl hydrazides (Eqs. 38 and 39).^[77] The proposed mechanism showed that t-BuOOH is first decomposed to tert-butoxy and tert-butylperoxy radicals with the assistance of iodine. The aryl sulfonyl radicals were generated by the t-BuOO•/t-BuO• mediated denitrogenation of the sulfonyl hydrazides, which then underwent the alkene addition and intramolecular cyclization cascade to form the products.

(Eq. 38)

(Eq. 39)

In 2018, Maity and co-workers reported an n-Bu₄NI/t-BuOOH mediated synthesis of γ-keto diesters 198 by an oxidative coupling between malonic esters 197 and styrenes (Scheme 43).^[78] The proposed mechanism showed that malonyl radicals 199 were first generated by the t-BuOO•/t-BuO• mediated hydrogen abstraction, which then underwent addition to styrene leading to the benzylic radical 200. The latter reacted with t-BuOO• to form the intermediate 201, which then underwent Kornblum–DeLaMare rearrangement to afford the product.

Scheme 43.

n-Bu₄NI/t-BuOOH mediated synthesis of γ-keto diesters by an oxidative coupling between malonic esters and styrenes.

Yuan and co-workers observed a solvent effect in an iodine-mediated coupling between sodium arylsulfinates and tert-amines (Scheme 44).^[79] The reaction presumably began with a hydrogen abstraction of the tertiary amine by either the tert-butoxyl radical or tert-butylperoxyl radical, followed by an electron transfer to form an iminium cation 202. When the reaction was carried out in an aqueous solution, a hydrolysis of 202 led to a secondary amine, which then coupled with the sulfonyl radical to furnish the sulfonamides. On the other hand, the intermediate 202 was converted to the enamine 203 by deprotonation in DMSO. Addition of the sulfonyl radical to 203 followed by iodination and HI elimination led to the β-arylsulfonyl enamines.

Scheme 44.

I₂-mediated chemoselective synthesis of sulfonamides and β-arylsulfonyl enamines.

Khan and co-workers reported an iodine-mediated oxidative cross-coupling of 4-hydroxydithiocoumarins 204 with primary amines.^[80] When anilines and alkyl amines were employed, 2-aminothio-4H-thiochromen4-ones 205 were obtained (Eq. 40). On the other hand, when polycyclic aromatic amines and heterocyclic amines bearing a highly nucleophilic α carbon next to the amino group, such as 2-naphthylamine and quinolin-6-amine, were used, sulfanes 206 were generated (Eq. 41). In addition, when thiols/thiophenols were employed, disulfides 207 were obtained (Eq. 42).

Liu and co-workers reported an I₂-catalyzed oxidative annulation of 3-cyanoacetylindoles 208 with benzylamines (Scheme 45).^[81] The proposed mechanism showed that the substrates first underwent a C–N bond coupling to generate the intermediate 209, which was oxidized to the iminium intermediate 210. A subsequent intramolecular cyclization led to the 5-(3-indolyl)oxazoles 211.

Scheme 45.

I₂-catalyzed oxidative annulation of 3-cyanoacetylindoles with benzylamines.

In 2016, Yang and co-workers reported an iodine-catalyzed oxidative functionalization of isoquinolines via a cascade N-alkylation and amidation of benzylic C–H bonds (Scheme 46).^[82] The proposed mechanism suggested that t-BuO–I and HO–I were first generated from the reaction between t-BuOOH and iodine. Subsequently, the benzylic C–H bond iodination took place via a t-BuO–I/HO–I mediated homolytic attack to generate benzyl iodide. The latter underwent a nucleophilic substitution with isoquinoline to afford the quaternary ammonium salt 212, which went through nucleophilic addition with t-BuOOH to afford intermediate 213. The latter underwent Kornblum–DeLaMare rearrangement to afford the isoquinolinone product.

Scheme 46.

I₂-catalyzed oxidative functionalization of isoquinolines.

Following Yang’s work, Reddy and co-workers later reported that a further iodination took place at the C4 position when the iodine reagent was increased from a catalytic to a stoichiometric amount, leading to C4-iodoisoquinolinones 214 (Eq. 43).^[83] On the other hand, when quinolines were employed, the reaction resulted in two regioisomers: 3-iodoquinolin-2(1H)-ones 215 and 3-iodoquinolin-4(1H)-ones 216, respectively, with the former slightly dominating (Eq. 44).

In 2019, Tan and co-workers reported an iodine-mediated synthesis of 2-thiazoles 218 from cysteine esters 217 and aryl aldehydes. The proposed mechanism involved a one-pot tandem cyclization and oxidation (Eq. 45).^[84] It’s worth noting that in the absence of both I₂ and t-BuOOH/(t-BuO)₂, the cyclization also occurred, though affording thiazolidines rather than thiazoles. By increasing the temperature from 70 °C to 120 °C and changing the solvent from 1,4-dioxane to DMF, the synthesis of 2-benzothiazoles 220 from 2-aminobenzenethiols 219 and aryl aldehydes was also accomplished with equal success.

(Eq. 45)

In 2019, Cui and Wu’s group developed an I₂/(t-BuO)₂-mediated tandem iodination, [3 + 2] cycloaddition, and nucleophilic addition reaction (Scheme 47).^[85] Using this strategy, two C–O bonds, three C–C bonds and one quaternary carbon center were constructed in one pot. The proposed mechanism showed that quinoline 1-oxide 221 a first underwent iodination at the C3 position (224) followed by a single-electron oxidative deprotonation by t-BuO• to generate intermediate 225. Subsequent 1,3-dipolar cycloaddition of N-ethylmaleimide 222 a with 225 produced intermediate 226, which underwent [1,5] sigma rearrangement and dehydroiodination afforded 227. Meanwhile, sequential 1,3-dipolar cycloaddition of 222 a with 221 a followed by the N–O bond cleavage afforded 228, which was then oxidized to 229. The nucleophilic addition of 227 to 229 led to 230, and subsequent dehydrogenation of 230 afforded product 223.

Scheme 47.

I₂-mediated tandem iodination, [3 + 2] cycloaddition, and nucleophilic addition.

Not only is t-BuOOH an oxidant but also a reactant in many iodine-mediated radical reactions. In 2015, Shah and co-workers reported an I₂-mediated oxidative amidation of terminal alkenes with amines (Eq. 46).^[86] The 1-iodomethyl aryl ketone 231 was proposed as the key intermediate which underwent nucleophilic substitution with amines and subsequent oxidation to afford the α-ketoamides. It is worth noting that the choice of the oxidant played a critical role in the reaction. When t-BuOOH was employed, the reaction took place with secondary amines at room temperature (Eq. 46). While, the reaction had to be heated to 80 °C when DMSO was used the oxidant (Eq. 47). In addition, in the case of primary amines, SeO₂ became the necessary oxidant (Eq. 48).

In 2018, Gao and Wang’s group reported an NH₄I/t-BuOOH-mediated iodoperoxidation of styrenes in an aqueous solution (Eq. 49).^[87] The reaction afforded the anti-Markovnikov addition product, α-iodo-β-peroxidates 232. On the other hand, the I₂-mediated iodoperoxidation of styrenes with t-BuOOH in decane led to the Markovnikov addition product, β-iodo-α-peroxidates 233 instead (Eq. 50). The authors proposed that the former reaction occurred via a free radical pathway, whereas the latter reaction took place via an ionic mechanism. It is worth noting that both aryl and aliphatic alkenes were well accommodated in the latter reaction but the former only accommodated aryl alkenes.

Abdukader and co-workers recently reported an iodine-mediated telescoping synthesis of α/β-aromatic peroxy thiols from styrenes and t-BuOOH (Scheme 48).^[88] In the presence of NH₄I, the reaction of styrenes, t-BuOOH, and thiophenol afforded (2-(tert-butylperoxy)-1-arylethyl)arylsulfane 235 via the key intermediate 234. While, in the presence of I₂, (2-(tert-butylperoxy)-2-arylethyl)arylsulfanes 237 were generated through the key intermediate 236. The proposed mechanism showed that in the presence of NH₄I and t-BuOOH, an addition of t-BuOO• to styrene first took place leading to the benzylic radical intermediate 238, which reacted with iodine radical to afford intermediate 234 a. Subsequent base-mediated nucleophilic substitution by thiophenoxide led to the α-sulfenyl-β-peroxidates. On the other hand, in the presence of I₂ and t-BuOOH, iodine first reacted with styrene to generate the benzylic radical intermediate 239, which then underwent cross coupling with t-BuOO• to afford intermediate 236 a. The latter underwent the base-mediated nucleophilic substitution by thiophenoxide led to the β-sulfenyl-α-peroxidates.

Scheme 48.

Iodine-mediated telescoping synthesis of α/β-aromatic peroxy thiols.

In 2019, Li and co-workers developed an I₂/t-BuOOH-mediated tandem annulation and oxidation of 1-(2-ethynylaryl)-prop-2-en-1-ones 240 (Scheme 49).^[89] The proposed mechanism showed that the reaction started from the iodine-mediated decomposition of t-BuOOH forming a hydroxyl radical. Addition of HO• to the alkyne led to the vinylic radical intermediate 242. Subsequent intramolecular cyclizations of 242 resulted in intermediates 243 and 244. The latter then underwent single-electron oxidative deprotonation to afford the dihydro-cyclopropanaphthalene-2,7-dione products 241. The control experiments employing either H₂¹⁸O or an oxygen atmosphere both suggested the oxygen atom of the new-formed carbonyl was from t-BuOOH.

Scheme 49.

I₂-mediated tandem oxidation-annulation of 1,6-enynes.

In 2021, Liu and Xu’s group reported an I₂-catalyzed synthesis of 1,2-diols/1,2-bisperoxides from styrenes and t-BuOOH (Scheme 50).^[90] In an aqueous solution, 1,2-diols 245 were obtained. The two oxygen atoms in the 1,2-diols came from H₂O and t-BuOOH, respectively. On the other hand, 1,2-bisperoxides 246 were formed in the presence of 10 mol% of Na₂CO₃ in propylene carbonate. Formation of t-BuOO• was proposed which underwent addition to styrene leading to a benzylic radical 247. 247 coupled with t-BuOO• to form 1,2-bisperoxides 246. On the other hand, in an aqueous solution, 247 underwent an intramolecular radical cyclization delivering the epoxide 248, which underwent water mediated ring-opening to afford the 1,2-diol 245.

Scheme 50.

I₂-catalyzed synthesis of 1,2-diols/1,2-bisperoxides from styrenes and t-BuOOH.

In 2023, Fernandes and co-workers reported an n-Bu₄NI-catalyzed difunctionalization of 1,3-dienes 249 with hydroperoxides for the synthesis of 1-peroxy-but-3-en-2-ols 250 (Scheme 51).^[91] The proposed mechanism showed that the tert-butylperoxyl radical generated from the catalytic cycle of n-Bu₄NI/t-BuOOH reacted with 1,3-dienes resulting in the formation of an allylic radical intermediate 251. The latter reacted with an iodine radical to form the intermediate 252, which underwent elimination of iodide to give the allylic carbocation 253. Finally, addition of H₂O to 253 generated 1-peroxy-but-3-en-2-ols 250.

Scheme 51.

n-Bu₄NI-catalyzed 1,2-difunctionalization of 1,3-dienes with hydroperoxides.

6. Conclusions

In this review, we have summarized the recent advances in the rapidly developing field of iodine-mediated free radical reactions reported between 2015 and mid-2024 and organized this article according to the mechanistic classification of the initiation steps taking place in the radical reactions. Notably, a variety of reaction conditions have been explored and well adapted in the field, including conventional heating, electrochemistry, and photocatalysis. A broad scope of chemical bonds and molecular scaffolds have been successfully prepared under environmentally friendly conditions, which further demonstrates the power of the iodine-mediated radical reactions.

On the other hand, despite the great progress made in this field, challenges still exist. First, the mechanistic studies of these reactions are far from enough, which hinders the wide application of the iodine-mediated radical reactions in organic synthesis. For example, similar reaction results often have different mechanistic explanations, and there is a lack of a universally accepted mechanism. Many iodine-mediated reactions display high regioselectivity, however, the reason for the high regioselectivity observed still remains to be further elucidated. We therefore expect that in future studies, more mechanistic studies on the iodine-mediated radical reactions should be carried out by both experimental and theoretical means. Second, there are only a few examples of iodine-mediated enantioselective syntheses, which is also a challenging topic for synthetic organic chemists. The few known examples all rely on the asymmetric organocatalysis strategy. Third, we expect that merging the iodine-mediated radical reaction pathways with the traditional transition metal-catalysis will further expand and enrich the reaction categories and mechanisms of organic chemistry, which will undoubtedly lead to the discovery of more new and exciting chemical reactivities and mechanisms. Therefore, we look forward to more breakthroughs in this emerging field.

Biographies

Wen Yang started his independent research career at Jiujiang University in 2021 after receiving his Ph. D. degree in organic chemistry in 2020 from South China Normal University and completing an assistant research fellowship at the Sun Yat-sen University. He was a visiting graduate student in the Chen Group at Queens College from 2015 to 2016. His recent research is focused on iodine-mediated reactions for synthesis of heterocycles.

Jian Guo earned his Bachelor’s degree in 2018 and his doctor’s degree in 2023 from Central South University. In autumn 2023, he joined Professor Yu Chen’s group as a post-doc at Queens College, the City University of New York. His research focuses on iodine catalyzed synthesis metholology.

Samual Hee obtained his BA in chemistry in 2022 from Macaulay Honors at Queens College. He is currently a graduate student in Dr. Yu Chen’s group at Queens college. He has previously been involved in projects about iodine catalyzed coupling reactions.

Yu Chen obtained both his B. Sc. and M. Sc. degrees from NanKai Univeristy. He then moved to the University of Toronto and pursued his Ph. D. degree with Prof. Andrei Yudin. Afterwards he joined Prof. Richard Larock’s group at the Iowa State University as a post-doctoral researcher. In 2009, he joined the faculty at Queens College and the Graduate Center of the City University of New York. His research interest includes late-transition-metal catalysis, iodine-mediated radical reactions, and heterocyclic chemistry.