Electrophilic Iodination of Organic Compounds Using Elemental Iodine or Iodides: Recent Advances 2008–2021: Part I

Abstract

The iodination of organic compounds is of great importance in synthetic organic chemistry. It opens comprehensive approaches for the synthesis of various biologically active compounds. The recent advances in iodination of organic compounds using elemental iodine or iodides, covering the last thirteen years, are the objective of the present review.

1. Introduction

The introduction of iodine as an available, inexpensive, environmentally friendly element into organic molecules has attracted a significant interest providing versatile building blocks in synthetic organic chemistry [1]. Iodine compounds have widespread use in organic chemistry. Iodinated compounds are frequently used as reagents in organic synthesis [2]. The best choice for the iodination of organic compounds is the use of molecular iodine or the iodide anion in combination with environmentally friendly and atom-efficient oxidants in the presence of desirable solvents or under solvent-free protocols, thus enhancing the green chemical profile of the iodination process [3]. Molecular iodine is extensively employed for α-iodination of alkyl carbonyl compounds [4]. It could act as a catalyst promoting enolisation and as a reagent reacting with enol to afford α-iodocarbonyl compounds [5]. Comprehensive synthetic protocols for electrophilic iodination of organic compounds employing I₂ or I⁻ were reviewed by Stavber and co-workers in 2008 [6]. The reports covered by this review [6] mainly carried low green chemical profiles, thus challenging greener-related protocols. Thus, in the present review, as part I of the matter, related protocols have been elaborated to highlight recent advances in the iodination of organic compounds, including alkanes, alkenes, alkynes, and alkyl carbonyls using elemental iodine or iodides, covering the period from 2008–2021.

2. Iodination of Alkanes

In 2008, Sudalai and co-workers [7] presented NaIO₄/KI/NaN₃ an efficient system for mono- and 1,2-difunctionalization of hydrocarbons through activation of C-H bond, providing vicinal azido- and acetoxy iodinations of cyclic hydrocarbons in high yields (Scheme 1). This protocol is successful for acyclic and cyclic alkanes.

Homolytic cleavage of I-N₃ gives an azide radical, which removes a proton from cyclic alkane to provide an alkyl radical. The reaction of an alkyl radical with I₂ provides alkyl iodide followed by oxidative elimination giving alkene, which undergoes addition of either I-N₃ or I-OAc across the double bond (Scheme 2).

In 2012, Yu and co-workers [8] reported diastereoselective C-H iodination with i-Pr- and t-Bu-substituted oxazoline auxiliaries catalyzed by palladium (II) (Scheme 3).

Zhu and co-workers [9] have presented quinoline-based ligand-enabled palladium (II)-catalyzed iodination of various α-hydrogencontaining carboxylic acid and amino acids (Scheme 4).

3. Iodination of Alkenes and Alkynes

The considerably breakthrough in the field of electrophilic iodination of alkenes was achieved already in 2005 [10], where, 30% aqueous H₂O₂ was used as the oxidant for the iodotransformation. However, later in 2008, Stavber and co-workers [11] even improved the green chemical profile of the reaction establishing an environmentally friendly methodology for aerobic oxidative iodination of alkenes using potassium iodide as iodine source catalyzed by sodium nitrite in acidic media providing the corresponding products in good to quantitative yields (Scheme 5). The authors have reported that the alkene was added as the last reactant to avoid polymerization. Moreover, in the case of phenyl-substituted alkynes (phenylethyne) using MeCN as the solvent, the formation of (E)-1,2-diiodo-1-phenyl-1-ethene was observed while, in the case of phenyl-1-propyne, a small amount of (Z)-1,2diiodophenylethene was also obtained (Scheme 6). The presence of an external nucleophile was observed to be beneficial for efficient and selective reactions.

Huang and Yang [12] have reported a novel and efficient method for synthesizing iodocyclopropylmethanol and 3-iodobut-3-en-1-ol derivatives via the iodohydroxylation of alkylidenecyclopropanes with I₂/H₂O system affording ring-opening or ring-keeping products in moderate to excellent yields (Scheme 7).

A convenient and eco-friendly method for the synthesis of α-iodoketones from alkenes and alkynes has been reported by Yadav and co-workers [13] using 2-iodoxybenzoic acid (IBX)/I₂ as the effective reagent system in water providing the corresponding products in good to high yields (Scheme 8).

The authors reported that the interaction between alkene and iodine could generate a cyclic iodonium ion, which reacts with water to provide an iodohydrin. The iodohydrin reacts with IBX to afford α-iodoketone (Scheme 9).

An efficient and facile protocol for the iodomethoxylation and iodohydroxylation of alkenes and alkynes in the presence of m-iodosylbenzoic acid as a recyclable reagent has been achieved by Chi and co-workers [14] (Scheme 10).

In the case of performing the reactions between alkynes and I₂/m-iodosylbenzoic acid/MeOH diiododimethoxylation products were obtained (Scheme 11).

By treatment of the reaction mixture with an anionic exchange resin, pure iodo-functionalized products were provided. Unreacted m-iodosylbenzoic acid and reduced m-iodobenzoic acid are regenerated from the resin by treatment with HCl.

A simple, efficient, and practical method for the iodination of alkynyl enolates has been described using allenoates as the starting material through an alkynyl enolate as the intermediate. The reaction of the silyl ether of alkynyl enolate with iodine provides iodoallenoate in good yield [15]. Grigg and co-workers [16] developed a protocol for the synthesis of 1-C-(tetra-O-acetyl-β-D-galactopyranosyl)-2,3-diiodo-1-propene using β-C-galactose allene as a starting material with iodine in the presence of ethanol as a solvent (Scheme 12).

A convenient method for synthesizing of vicinal halohydrins, haloacetates, and halo methyl ethers from olefins with 2:1 I⁻/${\mathrm{I}\mathrm{O}}_3^{-}$ has been described [17]. Iodo reagent was found to be better for reaction with linear alkenes and the elimination of diiodo impurity (Scheme 13). I⁻/${\mathrm{I}\mathrm{O}}_3^{-}$ was not successful for the vicinal functionalization of chalcones and stilbene.

Iodofluorination of electron-deficient olefins such as α,β-unsaturated esters, phosphonate, and amides with iodonium cation species generated by the anodic oxidation of iodide anion in Et₃N-5HF/MeNO₂ has been reported [18], providing the corresponding iodofluorinated products in good to moderate yields (Scheme 14).

An efficient route for the aerobic photo-oxidative synthesis of phenacyl iodides from styrenes, H₂O and I₂ has been reported by Itoh and co-workers [19], providing the corresponding products in moderate to high yields (Scheme 15).

A simple and efficient method for azidoiodination of alkenes has been reported by Sudalai and co-workers [20] using NaIO₄/KI/NaN₃ combination. Through an anti-Markovnikov fashion, the regiospecific 1,2-azidoiodination proceeds to give β-iodoazides in quantitative yields (Scheme 16).

NaIO₄ oxidizes both KI and NaN₃ to release I₂ and an azide radical, a combination of which gives IN₃. Homolysis of IN₃ affords an azide radical, which reacts with alkenes to form alkyl radical species. The combination of an alkyl radical with either molecular iodine or iodine radical affords β-iodoazides (Scheme 17).

Hanessian and co-workers [21] developed a method for the total synthesis of Jerangolid A (shows antifungal activity) where I₂ was used for iodination of lactone in the presence of pyridine in DMF underwent further steps. Kuhakarn and co-workers [22] have described the method for the direct synthesis of β-keto sulfones between the reaction of sodium arensulfinates with alkenes, including styrene derivatives, and aliphatic alkenes mediated by o-iodoxybenzoic acid/iodine (IBX/I₂) (Scheme 18).

A new route for synthesizing of 5-hydroxypyrrolin-2-one derivatives from the modified Morita-Baylis-Hillman (MBH) adducts through CuI- mediated aerobic oxidation, allylic iodination, hydration of nitrile, and lactamization has been reported [23].

Krasutsky and co-workers [24] have reported the method for electrophilic monoiodination of terminal alkenes (Scheme 19).

The use of the oxidative system (t-BuOCl + NaI) as an efficient oxidant and N-iodinating reagent with triflamide and cyclic dienes in acetonitrile for providing 1,1,1-trifluoro-N-((1R,5R)-5-iodocyclopent-2-en-1-yl)methanesulfonamide in low yield has been reported by Shainyan and co-workers [25]. A co-iodination method for alkenes with (diacetoxyiodo)benzene (DAIB) and I₂ combination and different nucleophilic sources (MeCN-nucleophile) providing the corresponding products in moderate to high yields have been reported [26] (Scheme 20).

Ma and co-workers [27] established stereoselective iodohydroxylation of 1,2-allenylic sulfoxides using iodine and benzyl thiol, providing 3-hydroxy-2-iodo-2(E)-alkenyl sulfides in the presence of MeCN/H₂O as a solvent.

[Bis(trifluoroacetoxy)iodo]benzene (PIFA) was used as a mediator for ethoxyiodination of enamides with potassium iodide, providing the corresponding products in good to quantitative yields [28]. A convenient method for the synthesis of vicinal iodohydrins and iodoesters from olefins has been reported by Narender and co-workers [29] via NH₄I and oxone system in MeCN/H₂O and DMF/DMA, under catalyst-free at room temperature, providing the corresponding products in good to quantitative yields. This protocol is realizable to various olefins, such as a terminal, symmetrical, and 1,2-disubstituted unsymmetrical olefins. Additionally, 1,2-disubstituted olefins provided excellent diastereoselectivity (Scheme 21).

The protocol for the synthesis of iodovinylnaphthols using molecular iodine in the presence of MeCN as the solvent has been developed by Kumar and co-workers (Scheme 22) [30].

Since halohydrins are essential building blocks in organic synthesis and could be transformed to other organic intermediates such as amino-, azidoalcohols, and epoxides, Ning and co-workers [31] established an efficient protocol of iodohydroxylation of olefins with DMSO (dimethylsulfoxide) as an oxidant, an oxygen source, a solvent and HI generated in situ. It was reported that DMSO could oxidize haloanions to halocations under acidic conditions (Scheme 23).

Zhu and co-workers [32] developed a one-pot and non-metal strategy for the direct vicinal difunctionalization of alkenes using iodine and tert-butyl hydroperoxide (TBHP) to synthesize 1-(tert-butylperoxy)-2-iodoethanes in good to high yields (Scheme 24). The method is realizable in the fields of organic synthesis, pharmacology, and medicinal chemistry.

Iodine monoacetate as an effective reagent was used for the regio- and diastereoselective iodoacetoxylation of alkenes and alkynes. An inexpensive, non-metal, and environmentally friendly protocol for synthesizing iodine monoacetate was presented using iodine and oxone in acetic anhydride and acetic acid combination. It was shown that the reactions with styrene derivatives were more successful than allylic and aliphatic olefins, where regioisomeric mixtures in lower yields were observed (Scheme 25). Additionally, alkynes provided mono- and diiodinations in comparable yields [33].

Liu and co-workers [34] developed the environmentally friendly method for the iodofunctionalization of olefins using I₂O₅ as the inorganic oxidant and LiI as the iodine source, in H₂O/acetone as the green solvent, providing the iodinated products in good to excellent yields (Scheme 26). The synthesis of different medicinal and agrochemical products could be realized through this method.

It is assumed that I₂O₅ oxidizes LiI to form HOI, which acts as a reactive electrophilic intermediate to cause the electrophile-mediated cyclization. If olefin is tethered with a nucleophilic center, intramolecular cyclization will occur. In contrast, when a substrate without a nucleophilic site was used, iodohydrin adducts were provided via the intermolecular nucleophilic attack of water onto the iodonium ions.

Shakhmaev and co-workers [35] have developed an efficient protocol for the synthesis of ethyl 5-phenylpent-2-en-4-ynoate by olefination-dehydrohalogenation of 2-iodo-3-phenylprop-2-enal obtained by the reaction between cinnamaldehyde and molecular iodine in the presence of 4-(dimethylamino)pyridine (DMAP) as the catalyst.

Meng and co-workers [36] have discovered a convenient and efficient method for iodination of arylacetylenes using I₂ and DMAP (4-dimethylaminopyridine) (Scheme 27) and the iodination of aryl acetylenic ketones by employing K₂CO₃ as a base providing the corresponding products in good to excellent yields (Scheme 28).

Tsai and co-workers [37] have established a simple and environmentally friendly method for iodination of terminal alkynes catalyzed by CuI/TBAB (tetrabutylammonium bromide) under air in water providing the corresponding products in good to high yields (Scheme 29).

The efficient method for iodoarylation of arylalkynes with I₂ and PhI(OCOPh)₂ was developed [38], providing the corresponding products in moderate to good yields (Scheme 30).

Reddy and co-workers [39] developed an efficient protocol for oxy-iodination of alkynes using potassium iodide (KI) and tert-butyl hydroperoxide (TBHP), in the presence of methanol as a solvent, at room temperature affording the corresponding products in moderate to quantitative yields (Scheme 31).

A novel and convenient protocol for the hydroiodination of alkynes has been established by Ogawa and Kawaguchi [40], employing I₂/hydrophosphine binary system affording the corresponding Markovnikov-type adducts in good yield. It was reported that this method could be applied for iodinations of OH and COOH groups. Chobanyan and co-workers have reported the method for the synthesis of hydroalumantion-iodination of alkyne-1,4-diols [41].

Guo and co-workers [42] have reported a new approach for the synthesis of (E)-diiodoalkenes using alkyne as the starting material, ammonium persulfate as an oxidant, iodide as iodine source, and water as the green solvent, providing the corresponding products in good to quantitative yields (Scheme 32).

It is assumed that oxidation of the iodide ion by the persulfate ion generates I₂, which further undergoes electrophilic anti-addition into the alkyne to afford the corresponding (E)-1,2-diiodoalkene (Scheme 33).

A convenient protocol for the iodination of N-propargyltriflamide between trifluoromethanesulfonamide and trifluoro-N-(prop-2-yn-1-yl)methanesulfonamide in the system t-BuOCl–NaI provided N-[(2E)-2,3-diiodoprop-2-en-1-yl]trifluoromethanesulfonamide has been described by Shainyan and co-workers [43]. Oxidative halogenation of terminal alkynes has been reported by Lui and co-workers [44] mediated by chloroamine salt as the oxidant and KI as the halogen source providing 1-iodooalkynes in good to quantitative yields (Scheme 34).

Inexpensive and non-toxic reagents NH₄I (iodide source) and oxone (oxidant) were used for stereospecific oxidative (E)-diiodination of various alkynes such as aliphatic, aromatic, and heteroaromatic alkynes at room temperature in the presence of water as a green solvent [45] (Scheme 35).

It is reported that oxone oxidizes the I⁻ (NH₄I) to form I⁺ (HOI). This reactive species may react with alkyne to give a transient cyclic iodonium species, which further undergoes nucleophilic attack by I⁻ in situ from the opposite side of the cyclic iodonium ion to provide trans-diiodo alkene.

Ferris and co-workers have reported an efficient method for the iodination of terminal alkynes [46], employing a stoichiometric amount of KI and CuSO₄ in a mix of MeCN and sodium acetate buffer solution (pH 5).

Bathophenanthrolinedisulfonic acid (BPDS) was used to solubilize copper species in the solution (Scheme 36).

Han and Xiao [47] have developed an efficient and simple procedure for double-iodination of terminal alkynes using I₂ in the presence of water as the green solvent at room temperature. Moreover, by employing I₂/H₃PO₃ system, the selective hydroiodination of different alkenes and alkynes were obtained in good yields (Scheme 37).

Regarding the mechanism, it was reported that H₃PO₃ could react with molecular iodine to give hydrogen iodide HI, and then following the Markovnikov rule, provides the corresponding hydroiodination. For the double-iodination, I₂ undergoes electronic anti-addition to alkynes via a cyclic iodonium to provide the corresponding diiodoalkene (Scheme 38).

In 2020, Ghosh and co-workers [48] reported a metal- and oxidant-free method for synthesizing 1,1,2-triiodostyrenes by decarboxylative iodination of propiolic acids using I₂/NaOAc providing the corresponding products in good yields (Scheme 39). Moreover, β,β-diarylacrylic acids undergo decarboxylative mono-iodination under the same reaction conditions, affording 1,1-diaryl-2-iodoalkenes.

In the same year, Lingling and co-workers [49] have published a convenient protocol for diiodination of alkynes employing sodium iodide (as iodine source) and air (as an oxidant) under the visible light, providing the corresponding products in moderate to high yields (Scheme 40).

Recently, an environmentally benign method for the aerobic oxidative iodination of terminal alkynes mediated by sodium sulfinate/KI was presented by Zhuo and co-workers [50] using ethanol as the green solvent at room temperature. Moreover, the synthesis of symmetrical 1,3-diynes was presented via the iodination/homocoupling of terminal alkynes (Scheme 41).

4. Iodination of Alkyl Carbonyls Compounds to α-Iodo Alkyl Carbonyl Derivatives

In 2008, Stavber and co-workers [11] had established an environmentally friendly methodology for aerobic oxidative α-iodination of carbonyl compounds using potassium iodide as iodine source catalyzed by sodium nitrite in acidic media providing the corresponding products in good to quantitative yields. In the case of aryl methyl ketones using MeCN as the solvent, iodination on the aromatic ring was occurred, while in the presence of aqueous EtOH as the solvent, the methyl group was iodinated (Scheme 42).

Pavlinac and co-workers [51] have described an efficient methodology for the iodination of dimethoxy- and trimethoxy benzenes, aryl alkyl ketones and cyclic ketones by employing I₂/UHP (urea-H₂O₂) or I₂/30% aq. H₂O₂ in the water miscible ionic liquid (IL) 1-butyl-3-methyl imidazolium tetrafluoroborate (bmimBF₄) or in water immiscible IL, 1-butyl-3-methyl imidazolium hexafluorophosphate(bmimPF₆), providing the corresponding products in excellent yields. In terms of efficiency, 30% aq. H₂O₂ was superior to UHP as the mediator of iodination in both ILs for iodine introduction at methoxy substituted benzenes and alkyl site next to a carbonyl group (Scheme 43).

The same group of authors have developed [52] the green methodology for iodination of aryl methoxy substituted 1-indanone, 1-tetralone, and acetophenone using I₂/30% aq. H₂O₂ as oxidant under solvent- and catalyst-free reaction conditions (SFRC). In the case of dimethoxy- and trimethoxy benzenes, iodination on the aromatic ring has occurred, while in the case of aryl alkyl ketones, iodination took place at the alkyl position next to a carbonyl group (Scheme 44).

Furthermore, Iskra and co-workers [53] have reported an efficient, selective, and metal-free protocol for the iodination of aldehydes, alkyl ketones, and aromatics using I₂/NaNO₂/air/silica-supported H₂SO₄ in MeCN at room temperature. Air was used as the oxidant for the regeneration of I₂ from eluted HI with 100% iodine atom economy (Scheme 45).

Yadav and co-workers [54] have reported a new and efficient method for the synthesis of α-iodo ketones and α-iodo dimethyl ketals in good to high yields, starting from acetophenones in the presence of I₂ and TMOF (trimethylorthoformate), (Scheme 46).

A convenient method for iodination of α,β-unsaturated ketones using copper (II) oxide/iodine in the presence of i-PrOH as the solvent has been reported by Wang and co-workers [55], providing the corresponding products in good to high yields (Scheme 47).

Terent’ev and co-workers [56] have reported the convenient method for synthesizing 2-iodo-1-methoxy hydroperoxides and their deperoxidation and demethoxylation to 2-iodo ketones. The reactions have occurred between enol ethers and the I₂-H₂O₂ system, providing the corresponding products in moderate to quantitative yields.

Stavber and co-workers [3] have established a novel and green methodology for iodination of ketones in an aqueous micellar system, in the presence of I₂, as the iodine source, air (terminal oxidant), NaNO₂ (catalyst), and H₂SO₄ (activator). The use of the aqueous solution of anionic amphiphile SDS (sodium dodecyl sulfate) was observed to be an excellent promoter than the use of water alone, improving the efficiency of the reactions (Scheme 48).

Lee and co-workers have developed an efficient method for iodination of aryl alkyl ketones using I₂/HTIB [hydroxyl(tosyloxy)iodo]benzene or MeI/HTIB in [bmim]BF₄ ionic liquid, providing the corresponding products in good to excellent yields [57].

An efficient protocol for the synthesis of α-iodo ketones by oxidative iodination of ketones in the presence of iodine and m-iodosylbenzoic acid as a recyclable oxidant has been presented. The corresponding iodinated products are separated from side products by treatment with anionic exchange resin Amberlite IRA 900 ${\mathrm{H}\mathrm{C}\mathrm{O}}_3^{-}$, m-iodosylbenzoic acid can be recovered from Amberlite resin by treatment with HCl [58].

A convenient and selective synthetic protocol for iodination of 1,3-dicarbonyl derivative substrates has been reported by Khan and Ali [59] using vanadyl acetylacetonate, hydrogen peroxide, and sodium iodide at ice-bath temperature, providing the iodinated products in good yields (Scheme 49).

Moriya and co-workers [60] have reported a convenient method for reductive iodination of carboxylic acids to alkyl iodides using 1,1,3,3-tetramethyldisiloxane (TMDS) and I₂ catalyzed by InBr₃ in the presence of CHCl₃ as the solvent.

Prebil and co-workers [61] have developed air/NH₄NO_3(cat.)/I₂/H₂SO_4(cat.) reaction system in the presence of MeCN as the solvent, for the α-iodination of aryl, heteroaryl, alkyl, and cycloalkyl methyl ketones. In the case of strongly activated aryl methyl ketones iodination took place regioselectively on the aromatic ring, (Scheme 50).

Regarding the mechanism, in cycle I, iodination enol form of the ketone at α-position using I₂ has occurred, and I₂ has been reduced to HI. The re-oxidation of iodide to I₂ by NO₂ has been presented as cycle II. NO₂ has been reduced to NO when it completes the oxidation of iodide, while the oxidation of NO to NO₂ is accomplished with aerial oxygen. Acidic conditions have two leading roles: the first is to transform NH₄NO₃ to HNO₃, which is thermally supported decomposing equilibrium with NO₂, and the second is in tuning the reactivity by increasing enolization of the ketone (Scheme 51).

In 2014, Terent’ev and co-workers [62] reported mono-and bicyclic enol ethers reactions with I₂/H₂O₂, I₂–Bu^tOOH, and I₂–tetrahydropyranyl hydroperoxide combinations. The authors have presented that the reaction pathway depends on the nature of peroxide and the ring size. The reaction between 2,3-dihydrofuran and 3,4-dihydro-2H-pyran with the I₂–hydroperoxide system provides iodoperoxides, α-iodolactones, and α-iodohemiacetals. Bicyclic enol ethers were converted into vicinal iodoperoxides only in the reaction with the I₂–H₂O₂ system (Scheme 52), while I₂–Bu^tOOH provides the hydroperoxidation product.

In 2011, Marri and co-workers [63] had reported a simple and efficient methodology for the α-monoiodination of carbonyl compounds employing NH₄I and oxone in methanol, providing the corresponding products in moderate to excellent yields (Scheme 53).

It is reported that Oxone^® oxidizes the I⁻ (NH₄I) to I⁺ (HOI) which reacts with enol form of carbonyl compound to provide the corresponding α-iodo product (Scheme 54).

In 2015, Reddy and co-workers [64] had established a convenient and environmentally friendly protocol for the synthesis of α-iodo alkyl ketones starting from secondary alcohols, including benzylic and aliphatic alcohols (cyclic and acyclic) using ammonium iodide and oxone in aqueous media (Scheme 55).

Zhu and co-workers have reported the convenient method for the β-C (sp³)-H iodination of ketones in the presence of palladium (II) as the catalyst employing aminooxyacetic acid auxiliary [65]. Sanz-Marco and co-workers [66] have developed an efficient and one-pot methodology for the synthesis of α-iodo alkyl ketones (as single constitutional isomers) starting from allylic alcohols and elemental iodine in combination with NaNO₂ as an oxidation catalyst and oxygen as the terminal oxidant. The protocol combines a 1,3-hydrogen shift mediated by Ir(III) complex (Scheme 56).

5. Conclusions

In summary, this review presents the progress of various methods for the iodination of organic compounds, including alkanes, alkenes, alkynes and alkyl carbonyls using elemental iodine or iodides. Aerobic oxidative and non-metal iodination strategies are also established. It should be emphasized that convenient methods have been developed in this field. Still, investigating and developing environmentally friendlier protocols in aqueous reaction media or under solvent-free can be considered an exciting research subject.