Iodonium ylides in organic synthesis

This review summarizes the chemistry of iodonium ylides with emphasis on their synthetic applications. The preparation, structure and chemistry of iodonium ylides of different structural types are overviewed. Iodonium ylides have found synthetic application as efficient carbene precursors, especially useful as reagents for cyclopropanation of alkenes and preparation of heterocyclic compounds. Recently iodonium ylides have been utilized as efficient reagents in the thiotrifluoromethylation and nucleophilic fluorination reactions

Previously we have published three reviews in Arkivoc summarizing synthetic applications of hypervalent iodine reagents 11,12 and aryliodonium salts. 13Aryliodonium ylides, ArI + --CX 2 , where X is an electron-withdrawing substituent (e.g., carbonyl or sulfonyl group), represent an important class of iodonium compounds with numerous applications in organic synthesis.5][16][17][18] In the present review, the synthesis and structural studies of iodonium ylides are discussed, and recent developments in their synthetic applications are summarized.The literature coverage is through Spring 2016.

Preparation and Properties of Iodonium Ylides
The first stable iodonium ylide was prepared from (difluoroiodo)benzene and dimedone by Neiland and co-workers in 1957. 19Since then, numerous stable aryliodonium ylides have been prepared and utilized as reagents for organic synthesis.
The vast majority of iodonium ylides have a relatively low thermal stability and can be handled only at low temperatures.The relatively stable dicarbonyl derivatives, PhIC(COR) 2 , [19][20][21][22][23] and the disulfonyl derivatives, PhIC(SO 2 R) 2 , [24][25][26][27] are generally prepared by a reaction of PhI(OAc) 2 with appropriate dicarbonyl compounds or disulfones under basic conditions.In particular, phenyliodonium ylides 2 are obtained by the treatment of malonate esters 1 with (diacetoxyiodo)benzene in dichloromethane in the presence of KOH (Scheme 1). 22An optimized procedure for the preparation of bis(methoxycarbonyl)(phenyliodonium)methanide 4 by a similar reaction of dimethyl malonate 3 in acetonitrile was published by the same authors in Organic Syntheses. 28Ylides 2 and 4 can be stored for several weeks at -20 o C, however, they slowly decompose at room temperature.Scheme 1. Synthesis of iodonium ylides from malonate esters.
Zhang and co-workers have reported a convenient procedure for the preparation of dimedone-derived iodonium ylide 6 in excellent yield by treatment of dimedone 5 with iodosylbenzene in dichloromethane (Scheme 2). 29Addition of a catalytic amount of zinc perchlorate (10 mol%) shortens the reaction time to 10 min with a slightly lower yield (80%) yield of ylide 6. Zinc cation acts as a Lewis acid depolymerizing and activating iodosylbenzene.Scheme 2. Synthesis of dimedone-derived iodonium ylide 6.
Practical applications of ylides 2, 4 and 6 are limited by their poor solubility (insoluble in most organic solvents except DMSO) and low stability.Thermal stability and solubility of iodonium ylides can be significantly improved by introduction of a coordinating substituent in the ortho position of the phenyl ring. 30In particular, 2-alkoxyphenyliodonium ylides 9 derived from malonate methyl ester and bearing an ortho alkoxy substituent on the phenyl ring, can be synthesized from commercially available 2-iodophenol 7 via diacetates 8 according to the procedure shown in Scheme 3. Ylides 9 are relatively stable compounds with excellent solubility in dichloromethane, chloroform, or acetone (e.g., the solubility of ylide 9, R = Pr, in dichloromethane is 0.56 g/mL). 31The higher thermal stability and a useful reactivity pattern are also characteristic for the dimedone-derived o-alkoxyphenyliodonium ylides 10, which are prepared similarly by the reaction of diacetates 8 with dimedone 5 in methanol in the presence of KOH (Scheme 3). 32Scheme 3. Synthesis of 2-alkoxyphenyliodonium ylides.
Recently, several stable ortho-substituted iodonium ylides 13 have been prepared by reactions of -dicarbonyl compounds 11 with benziodoxole 12 in the absence of any base (Scheme 4). 33The new iodonium ylides 12 bearing an ortho-propan-2-ol group in the phenyl ring are surprisingly stable for acyclic iodonium ylides owing to the intramolecular coordination of iodine by the hydroxyl group.Not only are these iodonium ylides stable at room temperature, but they could be purified by column chromatography on silica gel.Scheme 4. Synthesis of iodonium ylides 13 from benziodoxole 12.
Cyclic iodonium ylides, in which the iodonium atom is incorporated in a five-membered ring, have even higher thermal stability.The unusually stable cyclic iodonium ylides 16 were prepared via the intramolecular transylidation of the acyclic ylides 15, which were synthesized by the known method from -diketones 14 (Scheme 5). 34Scheme 5. Synthesis of cyclic iodonium ylides 16.
Cardinale and Ermert have developed a simplified method for preparing aryliodonium ylides in a one-pot procedure starting from the respective aryl iodides. 23In particular, aryliodonium ylides 19 were synthesized by a two-step, one-pot procedure shown in Scheme 7. Aryl iodides were first oxidized with m-chloroperoxobenzoic acid (mCPBA) in dichloromethane followed by the addition of Meldrum's acid (2,2-dimethyl-1,3-dioxane-4,6-dione) and KOH to give ylides 19 in moderate yields. 23heme 7. Preparation of aryliodonium ylides in one-pot starting from aryl iodides.
Ochiai and co-workers developed a new synthetic approach to iodonium ylides 21 by the intermolecular transylidation reactions between halonium ylides under thermal or catalytic conditions (Scheme 8). 36,37The transylidation of bromonium 20 to iodonium 21 ylides proceeds under thermal conditions and probably involves generation of a reactive carbene intermediate. 36eating of phenyliodonium ylide 22 with iodoarenes in the presence of 5 mol% of rhodium(II) acetate as a catalyst results in the transfer of the bis(trifluoromethylsulfonyl)methylidene group to the iodine(I) atom of iodoarene to afford substituted aryliodonium ylides 23 in good yields. 37Scheme 8. Preparation of aryliodonium ylides by the intermolecular transylidation reactions.
Iodonium ylides derived from phenolic substrates represent an important class of zwitterionic iodonium compounds. 17,18The preparation of phenolic iodonium ylides 24 was first reported in 1977 via a reaction of para-substituted phenols with (diacetoxyiodo)benzene followed by treatment with pyridine (Scheme 9). 38The system of an iodonium phenolate is stabilized by the presence of at least one electron-withdrawing substituent on the aromatic ring.Monosubstituted iodonium phenolates 24 are relatively unstable and easily rearrange to iodo ethers 25 under heating.

Scheme 9. Preparation and rearrangement of phenolic iodonium ylides.
Mixed phosphonium-iodonium ylides represent a useful class of reagents that combine in one molecule synthetic advantages of a phosphonium ylide and an iodonium salt.The preparation of the tetrafluoroborate derivatives 27 by the reaction of phosphonium ylides 26 with (diacetoxyiodo)benzene in the presence of HBF 4 was first reported by Neilands and Vanag in 1964. 39Later, in 1984, Moriarty and co-workers reported the preparation of several new tetrafluoroborate derivatives 29 and X-ray crystal structure for one of the products. 403][44][45] The analogous mixed arsonium-iodonium ylides were synthesized using a similar procedure. 45Preparation of heteroaryl-substituted phosphonium-iodonium ylides was also reported. 46][49][50][51][52] Scheme 10. Preparation of mixed phosphonium-iodonium ylides.Scheme 11.Generation of monocarbonyl iodonium ylides.

General Structural Features of Iodonium Ylides
Single crystal X-ray structures have been reported for the following iodonium ylides: 3phenyliodonio-1,2,4-trioxo-1,2,3,4-tetrahydronaphthalenide 33, 53 3-phenyliodonio-2,4-dioxo-1,2,3,4-tetrahydro-1-oxanaphthalenide 34, 53 mixed phosphonium-iodonium tetrafluoroborates 35 40 and 36, 43 mixed arsonium-iodonium tetrafluoroborate 37, 54 mixed phosphonium iodonium triflate 38, 42 phenyliodonium bis(trifluoromethanesulfonyl)methide 39, 24 cyclic iodonium ylide 40, 34 2-methoxyphenyliodonium bis(methoxycarbonyl)methanide 41, 31 and the pseudocyclic ortho-substituted iodonium ylides 42 33 (Figure 1).According to X-ray data, the geometry of aryliodonium ylides is similar to the geometry of iodonium salts with a C-I-C angle close to 90 o , which is indicative of a zwitterionic nature of the ylidic C-I bond.In particular, phenyliodonium ylide 39 has a geometry typical for an iodonium ylide with the I-C ylidic bond length of about 1.9 Å and an C-I-C bond angle of 98°. 24X-ray structural analysis for cyclic ylide 40 reveals a distorted five-membered ring with the ylidic bond length about 2.1 Å and a C-I-C bond angle of 82°, which is smaller than the usual 90°. 342-Methoxyphenyliodonium bis(methoxycarbonyl)methanide 41 in solid state has a polymeric, asymmetrically bridged structure with a hexacoordinated geometry around the iodine centers formed by two short C-I bonds [2.117 Å for I-C(Ph) and 2.039 Å for I-C(malonate)] and two relatively long iodine-oxygen intramolecular interactions between iodine and the oxygen atom of the ortho substituent (2.928 Å) and the carbonyl oxygen atom of the methoxycarbonyl group (3.087 Å).In addition, a relatively weak intermolecular I-O secondary interaction of 2.933 Å between the iodine center and the carbonyl oxygen atom of the neighboring molecule is also present in the solid state structure of 41. 31 Structure of the unusually stable pseudocyclic iodonium ylide 42 bearing an ortho-propan-2-ol group in the phenyl ring is characterized by the presence of additional intramolecular coordination of iodine by the hydroxyl group. 33The structures of iodonium ylides have also been studied by various spectroscopic techniques.For example, an interesting Moessbauer spectral study has been published by Nishimura and coauthors. 55This study, in particular, confirmed that the ylidic I-C bond is mostly zwitterionic in nature.
In should be mentioned that the ylidic bond in iodonium ylides is commonly shown in the literature as the I=C double bond.However, according to high level computational study using adaptive natural density partitioning bond modeling technique (AdNDP), a double bond between iodine atom and other elements does not exist and the actual bonding in iodonium ylides has a dative 2c-2e nature. 56
A particularly useful reagent in these carbenoid reactions is the highly soluble and reactive iodonium ylide 45 derived from malonate methyl ester and bearing an ortho methoxy substituent on the phenyl ring. 31This reagent shows higher reactivity than common phenyliodonium ylides in the Rh-catalyzed cyclopropanation, C-H insertion, and transylidation reactions under homogeneous conditions.Examples of the carbenoid reactions of ylide 45 are shown in Scheme 13. 31 Scheme 13.Carbenoid reactions of the soluble iodonium ylide 45.
5][16] The product composition in the rhodium(II)-catalyzed reactions of iodonium ylides was found to be identical to that of the corresponding diazo compounds, which confirms that mechanisms of both processes are similar and involve metallocarbenes as key intermediates. 69Hadjiarapoglou and co-workers have recently reported a mechanistic study of the reactions of cyclic β-dicarbonyl phenyliodonium ylide with various substituted styrenes under Rh 2 (OAc) 4 catalysis confirming the carbenoid mechanism of these reactions. 70][86] Moriarty and co-workers have investigated the intramolecular cyclopropanation of iodonium ylides to the tricyclic ketones in the presence of copper(I) chloride and also in the absence of conventional metal calalysts. 87Synthetic utility of this methodology has been demonstrated by conversion of ylide 46 to a mixture of diastereomeric products 47 and 48 related to prostaglandins and vitamin D, respectively (Scheme 14).

Scheme 15. Enantioselective intramolecular C-H insertion of phenyliodonium ylide 49.
Charette and co-workers have developed a Cu(I)-catalyzed asymmetric cyclopropanation of alkenes with an iodonium ylide generated in situ from iodosylbenzene and methyl nitroacetate (Scheme 16). 74High enantioselectivity (up to 98% ee) and diastereoselectivity (95:5 dr trans/cis) were achieved for a wide range of aryl-or alkyl-substituted alkenes 51.This synthetically useful reaction allows facile preparation of various 1-nitrocyclopropyl carboxylates 52 which can be further transformed into the corresponding substituted cyclopropane amino acids and aminocyclopropanes.

Scheme 19. Darzens-type condensation of alkenyliodonium salt with aromatic aldehydes.
Murphy and co-workers have investigated the suitability of monocarbonyl iodonium ylides as metallocarbene precursors. 89They have developed a new method for generating monocarbonyl iodonium ylides 61 in situ by treatment of phosphonium ylides 60 with iodosylbenzene.Ylides 61 were subsequently intercepted by transition-metal catalysts to generate metallocarbenes, which then underwent either dimerization or cyclopropanation reactions with alkenes (Scheme 20).Though the authors were unable to improve the yields of cyclopropanes 62 to be synthetically viable, this study proves that monocarbonyl iodonium ylides 61 can serve as metallocarbene precursors.Scheme 20.Reactions of monocarbonyl iodonium ylides as metallocarbene precursors.

Cycloaddition reactions of iodonium ylides leading to heterocycles
Iodonium ylides of different structural types have been used in various heterocyclization reactions under transition metal free conditions or in the presence of metal catalysts.Liang and co-workers have developed a metal-free approach to synthesis of indolines from N-(orthochloromethyl)aryl amides and iodonium ylides. 97n particular, N-[2-(chloromethyl)phenyl]tosylamides 66 react with iodonium ylides 67 at room temperature to afford indolines 68 in moderate yields (Scheme 22).The mechanism of these reactions involves the initial conversion of N- [2-(chloromethyl)phenyl]tosylamides into the aza-o-quinodimethane intermediate under basic conditions, followed by Michael addition and N-alkylation with iodonium ylide to generate indoline by loss of iodobenzene. 97cheme 22. Synthesis of indolines from N-(ortho-chloromethyl)aryl amides and iodonium ylides.
Liang, Li and co-workers have also reported a mild and general synthesis of benzofurans by cycloaddition of arynes with iodonium ylides. 98The aryne intermediates, generated from 2silylaryltriflates 69 in the presence of CsF, undergo the cycloaddition reaction with iodonium ylides 70 at room temperature to afford the corresponding benzofurans 71 in moderate to good yields (Scheme 23).

Scheme 23. Synthesis of benzofurans by cycloaddition of arynes with iodonium ylides.
Stabilized -dicarbonyl iodonium ylides 72 react with isocyanates 73 under mild conditions to afford substituted oxazolin-2-ones 74 in moderate yields (Scheme 24). 99It has been suggested that this reaction proceeds via carbenoid intermediates, as supported by isolation of the products of carbene dimerization from the reaction mixture.Scheme 24.Synthesis of oxazolin-2-ones from isocyanates and iodonium ylides.
A modified, o-alkoxy-substituted ylide 76, has an improved solubility in nonpolar solvents, such as aromatic hydrocarbons, and has a generally higher reactivity compared to ylide 75. 32Ylide 76 is a useful reagent for the preparation of oxazole derivatives 78 in the reaction with carbodiimides 77 under homogeneous conditions in the presence of Rh(II) or Cu(II) catalysts (Scheme 26). 32Scheme 26.Synthesis of oxazole derivatives using stabilized phenyliodonium ylide 76.
The reactions of heteroaryl-substituted (in the phosphonium part) phosphonium-iodonium ylides 80 with alkynes afford either furyl annelated phosphinolines 81 or phosphonium substituted furans 82 depending on the nature of the substituent R in the alkyne (Scheme 28). 46,117The authors proposed a mechanism involving the initial elimination of PhI upon UVirradiation with the formation of an electrophilic intermediate, which interacts with the alkyne to give the corresponding products of cationic cyclization.Scheme 28.Reactions of heteroaryl-substituted phosphonium-iodonium ylides 80 with alkynes.

Introduction of fluorine using iodonium ylides
9][120][121] Iodonium ylides have an advantage over diaryliodonium salts as the selective PET precursors.Due to the carbanionic character of the ylidic carbon, the attack of an external nucleophile in principle should be directed exclusively toward the aromatic ring of the Ar group of an aryliodonium ylide.However, it was previously demonstrated that the reaction of various organic and inorganic acids with phenyliodonium ylides leads to nucleophilic substitution of the iodobenzene substituent by the anion. 122,123Gondo and Kitamura have recently reported that the reaction of iodonium ylides 83 derived from 1phenylbutan-1,3-dione, ethyl benzoylacetate, and ethyl p-nitrobenzoylacetate with Et 3 N•3HF gave the corresponding fluorinated products 84 in low yields (Scheme 29). 124These products are formed through the C-protonation of the ylide, followed by displacement of the PhI by the fluoride ion.In sharp contrast to the reactions of aryliodonium ylides with acids, Satyamurthy and Barrio have found that the reactions of ylides with nucleophiles (F -, Cl -, Br -, etc.) in polar aprotic solvents such as acetonitrile, tetrahydrofuran, dimethylsulfoxide, dimethylacetamide and dimethylformamide lead to regioselective substitution of the nucleophile on the aromatic ring instead of the dione ring. 125For example, heating of phenyliodonium ylides 88 with dried KF-Kryptofix (K 222 ) complex in dry DMF affords fluoroarenes 89 as main product and hydrocarbon 90 as a byproduct due to a radical channel competing with the nucleophilic substitution reaction (Scheme 31).No product of fluorination of the -dicarbonyl moiety has been detected in this reaction. 125heme 31.Reaction of iodonium ylides with fluoride anion in DMF.This approach has been employed for the radiofluorination of protected L-DOPA derivatives. 125A radiochemically pure amino acid L-6-[ 18  Vasdev, Liang, and co-workers have demonstrated that the spirocyclic hypervalent iodine(III) ylides can serve as synthetically versatile precursors for efficient radiolabelling of a diverse range of non-activated (hetero)arenes, highly functionalized small molecules, building blocks, and radiopharmaceuticals from [ 18 F]fluoride ion. 126,127In particular, the reactions of ylides 92 and 94 under continuous-flow microfluidic condition offers automated synthetic procedure for the preparation of a radiopharmaceutical, 3-[ 18 F]fluoro-5-[(pyridin-3yl)ethynyl]benzonitrile ([ 18 F]FPEB) 93, and a routinely used building block for clickradiochemistry, 4-[ 18 F]fluorobenzyl azide 95 in 68% radiochemical conversion (RCC) (Scheme 33).

Thiotrifluoromethylation using iodonium ylides
In 2013, Shibata and co-workers have introduced a novel electrophilic-type trifluoromethylthiolation reagent, trifluoromethanesulfonyl iodonium ylide 96, which can react with various nucleophiles to afford CF 3 S-substituted products 97 (Scheme 34). 128These reactions have a complex mechanism involving in situ reduction of the trifluoromethanesulfonyl group in the presence of a copper catalyst to give the trifluoromethylthio group.The key steps of this mechanism are shown in Scheme 34.Scheme 34.Copper-catalyzed trifluoromethylthiolations by iodonium ylide 96.

Scheme 35. Thiotrifluoromethylation of indoles.
In a series of more recent publications, reagent 96 has been used for thiotrifluoromethylation of various other nucleophilic substrates, such as: allyl alcohols and boronic acids, 129 arylamines, 130 allylsilanes and silyl enol ethers, 131 and pyrroles. 132Several examples of thiotrifluoromethylation reactions of these substrates are shown in Scheme 36.

Conclusions
This review demonstrates that iodonium ylides of different structural types are becoming increasingly popular reagents in organic synthesis.Iodonium ylides are widely used as efficient carbene precursors, especially useful as reagents for cyclopropanation of alkenes and preparation of heterocyclic compounds.Recently iodonium ylides have been utilized as efficient reagents in the thiotrifluoromethylation and nucleophilic fluorination reactions, which find practical application in Positron Emission Tomography.We anticipate that this synthetically important area of hypervalent iodine chemistry will continue to attract significant research activity in the future.