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Synthesis 2015; 47(05): 587-603
DOI: 10.1055/s-0034-1379892
review
© Georg Thieme Verlag Stuttgart · New York

Reagent and Catalyst Design for Asymmetric Hypervalent Iodine Oxidations

Florian Berthiol*
Département de Chimie Moléculaire (SERCO), UMR-5250, ICMG FR-2607, Université Joseph Fourier, 301 Rue de la Chimie, BP 53, 38041 Grenoble Cedex 9, France   Email: Florian.Berthiol@ujf-grenoble.fr
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Further Information

Publication History

Received: 30 October 2014

Accepted after revision: 20 November 2014

Publication Date:
28 January 2015 (online)

 
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Abstract

In this review are compiled the different possible transformations using environmentally benign chiral hypervalent iodine reagents and catalysts. Herein is presented an overview of asymmetric oxidation of sulfides to sulfoxides, oxidation of alkenes, α-functionalization of carbonyl compounds and dearomatization reactions.

1 Introduction

2 Chiral Hypervalent Iodine Reagents

3 Oxidation of Sulfides to Sulfoxides

4 Oxidation of Alkenes

5 α-Functionalization of Carbonyl Compounds

6 Dearomatization Reactions

7 Conclusion


#

Key words

hypervalent iodine - asymmetric transformations - homogeneous organocatalysis - oxidations - carbon–carbon bond formations - carbon–heteroatom bond formations

Biographical Sketch

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Florian Berthiol was born in Guilherand-Granges (Close to Valence, France) in 1979. He studied chemistry at the University of Marseille. He obtained his PhD in the group of Maurice Santelli and Henri Doucet in 2005, working on the application of a novel palladium complex in various cross-coupling reactions. He then received a JSPS postdoctoral grant and moved to Tokyo University in the group of Shū Kobayashi, where he investigated the use of enamides and sulfonylimidates as nucleophiles. Two years later, he joined the group of Johannes­ G. De Vries and Ben L. Feringa at the University of Groningen, working on dynamic kinetic resolution. After one year, he returned to France at the University of Lyon in the group of Olivier Baudoin, using C–H activation reactions in total synthesis. He was then appointed Chargé de Recherche (CNRS) at the University of Grenoble, in the group of Dr Jacques Einhorn­, in 2009. He is currently developing new chiral NHPI analogues and chiral hypervalent iodine oxidation organocatalysts.

1

Introduction

The first organic hypervalent iodine was prepared by Willgerodt in 1886,[1] [2] but it is only in the past three decades that hypervalent iodine reagents and catalysts have been developed and used in organic chemistry.[3] The unique characteristics of the iodine render its use very attractive. Iodine can be easily oxidized into either hypervalent λ3- or λ5-iodanes, with these reagents able to induce different transition-metal-like transformations, such as oxidation reactions,[4] [5] carbon–carbon or carbon–heteroatom bond formations.[6] [7]

In λ3-iodanes 1, the iodine atom possesses ten valence electrons and exhibits distorted trigonal bipyramid geometry (Figure [1]). The two heteroatomic ligands X occupy the apical positions, while the carbon ligand R and both electron pairs are in equatorial positions. As X–I–X is a linear three-center four-electron (3c-4e) bond, both I–X bonds are highly polarizable and thus are longer and weaker than a regular covalent bond. During the oxidation process, there is usually a ligand exchange followed by a reductive elimination, with both heteroatom ligands X serving as leaving groups.[8] Iodonium salts 2 also belong to the λ3-iodane class[9] with pseudo-trigonal bipyramid geometry. They possess an ionic part X closely associated to the iodine and two carbon ligands R with an R–I–R bond angle close to 90°.

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Figure 1 Hypervalent λ3- and λ5-iodane geometries and commercially available examples

In λ5-iodanes 3, the iodine atom possesses twelve valence electrons and exhibits distorted octahedral geometry (Figure [1]). The carbon ligand R and the electron pair occupy the apical positions, and the four heteroatomic ligands X take up the basal positions. In this structure all ligands X are accommodated by two orthogonal hypervalent 3c-4e bonds, the apical carbon ligand R being attached to the iodine by a normal covalent bond.[10] [11]

Organoiodines are quite reactive toward many classical oxidants and can be easily transformed into organoiodanes.[4] In some cases the oxidation of organoiodines predominates over oxidation of organic functional groups. For example, the simple presence of a catalytic amount of aryliodine in a mixture of propiophenone and m-chloroperbenzoic acid will prevent the Baeyer–Villiger reaction from occurring (section 5), and in a mixture of alkene and m-chloroperbenzoic acid it will prevent epoxidation of the double bond (sections 4 and 6).

Before the last decade, the iodanes were prepared and isolated prior to being used in stoichiometric quantities in oxidation reactions. In fact, only a few oxidants are able to reoxidize the aryl iodide into the hypervalent iodine(III) or iodine(V) species in situ. The most commonly used stoichiometric oxidant is m-chloroperbenzoic acid, which has been employed in almost all publications reporting the use of hypervalent iodines as organocatalysts. Only two other stoichiometric oxidants have been employed successfully: hydrogen peroxide (by Ishihara and co-workers[12] in 2010) and more recently sodium perborate (by Wirth and co-workers[13]).

One of the great advantages of using these reagents is their low toxicity compared to other halogen-based reagents and especially compared to transition-metal catalysts with comparable reactivity, thus making them perfectly suitable for green and environmentally benign applications. Some of these reagents are commercially available (Figure [1]), like the λ3-iodanes PIDA[14] and PIFA,[15] and the λ5-iodanes IBX[16] and DMP,[17] and are now commonly used in numerous reactions. Another advantage is the possibility to introduce a covalent chiral backbone on the iodine, which is impossible with transition-metal species with similar reactivity.

For all the reasons mentioned above, the development of chiral versions of hypervalent iodine reagents and catalysts has drawn particular attention in recent years.[18] In this review are discussed the design of such chiral reagents and catalysts and their use in mainly four types of reactions: oxidation of sulfides to sulfoxides, oxidation of alkenes, α-functionalization of carbonyl compounds and dearomatization reactions.


# 2

Chiral Hypervalent Iodine Reagents

The first chiral hypervalent iodine reagent was synthesized by Imamoto and Koto in 1986.[19] For the first time, moderate enantioselectivities were obtained in the metal-free oxidation of sulfides. This first example was the prelude to the development of several hypervalent iodine reagents, catalysts and precursors (Figure [2]).

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Figure 2 Different existing structures of hypervalent iodine reagents, catalysts or precursors

In the first reagents synthesized by Imamoto and Koto,[19] Koser and Ray,[20] [21] and Chen and Xia,[22] the chiral substituent was always placed onto an oxygen, this oxygen being the ligand of the iodine. However, an oxygen-ligand exchange generally occurs under oxidation conditions;[17] along with this comes the possibility of losing the chiral oxygen ligand in the process, thus inhibiting the further development of a catalytic version of the reaction. Wirth and Hirt reported in 1997 the first example of chiral hypervalent iodine reagent, bearing the chirality on the carbon backbone of an aryl ligand, that was effective in oxidation reactions.[23] Numerous structurally different aryl iodides have been synthesized since then. In 2005, Ochiai et al.[24] and Kita and co-workers[25] independently reported the first achiral catalytic oxidation reactions using aryl iodides as organocatalysts and m-chloroperbenzoic acid as the stoichiometric oxidant (Scheme [1]). The first catalytic asymmetric version was finally reported by Wirth and co-workers in 2007.[26]

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Scheme 1 First oxidation reactions catalyzed by a hypervalent iodine organocatalyst by Ochiai et al. (a) and Kita et al. (b)

In the chemistry of chiral hypervalent iodine oxidations, there are mainly three types of chiral induction that have been exploited in order to achieve enantioselective transformations. The first and most common is to place a chiral moiety on one of the ligands of the iodine, with in most cases one or more heteroatoms that are capable of halogen bonding to bring the chirality closer to the iodine center (Figure [2, 5–7, 9–11, 14, 15, 17, 18, 20]). The second is to use a biphenyl or binaphthyl ligand on the iodine, thus inducing the chirality by atropoisomerism (Figure [2, 8, 12, 13, 19, 22]). The third is to have a racemic hypervalent iodine reagent in anionic form and to induce chirality by using a bulky chiral counter-cation (Figure [2,] 16 and 21). The anion can be simple iodide anion or a more complex structure bearing a negative charge not onto the iodine but close to it.

All these reagents have been used in mainly four types of reactions that are described in the next sections.


# 3

Oxidation of Sulfides to Sulfoxides

Enantiopure sulfoxides are widely used as chiral auxiliaries in a broad range of reactions.[27] The first example of asymmetric oxidation of sulfide to sulfoxide using a chiral hypervalent iodine reagent was described by Imamoto and Koto in 1986.[19] In this pioneering work, they prepared in situ chiral λ3-iodanes 4′ combining iodosylbenzene with tartaric anhydride derivatives. These reagents were shown to oxidize sulfides 27 to sulfoxides 28 with good yields and up to 53% ee (Scheme [2]). The authors prepared another catalyst combining iodosylbenzene with two tartaric acid monoesters which gave poor enantioselectivity. From this result, they assumed that the catalyst shape had to be a C 2-symmetric seven-membered-ring system, this thus being a determining factor in the efficiency of the chiral induction.

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Scheme 2 First asymmetric oxidation of sulfides to sulfoxides by a chiral hypervalent iodine reagent

However, Koser and Ray showed in 1992 that the combination of iodosylbenzene or (diacetoxyiodo)benzene with tartaric anhydride derivatives led to polymeric structures 4.[20] The obtained polymers were used in the oxidation of methyl phenyl sulfide and the corresponding sulfoxide was obtained with similar ee (30% ee vs 36% in Imamoto’s case; Scheme [3]).

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Scheme 3 Real form of the reagent obtained by reaction between iodosylbenzene and dibenzoyltartaric acid, and its use in the oxidation of sulfides to sulfoxides

In 1999, Kita and co-workers reported the first example of catalytic asymmetric oxidation of sulfides to sulfoxides.[28] Various sulfides were oxidized to the corresponding sulfoxides with excellent yields and moderate enantioselectivities in a cationic reversed-micellar system (Scheme [4]). In this example the racemic iodylbenzene was used as the stoichiometric oxidant and tartaric acid was used as the ligand and chiral inductor. The authors play upon the low solubility of unsubstituted iodylbenzene which was unable to perform the racemic oxidation: when complexed to the tartaric acid derivative, the newly formed hypervalent reagent became soluble in the solvent and performed the asymmetric transformation. In this system, the toluene-to-water ratio was critical: without water the reaction did not proceed at all and with a greater amount of water the reversed micelles were not formed, thus the reaction proceeded via classical phase-transfer catalysis and resulted in a lower enantioselectivity.

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Scheme 4 First catalytic oxidation of sulfides to sulfoxides by a hypervalent iodine catalyst; CTAB = cetyltrimethylammonium bromide

One year later, the same research group succeeded in using water as the only solvent. They used magnesium bromide to enhance the enantioselectivity in their new system, obtaining excellent yields (84–100%) and moderate enan­tio­selectivities (43–63%).[29]

In 2006, Quideau and Ozanne-Beaudenon employed SIBX, a stabilized version of IBX, combined with different chiral additives for the asymmetric oxidation of sulfides.[30] Using similar conditions and the same additive as Kita et al., the expected sulfoxides were obtained with up to 50% ee.

In 1990, Koser and Ray developed another type of chiral hypervalent iodine reagent: {[(+)-menthyloxy](tosyloxy)iodo}benzene.[21] They combined this reagent with sulfides to obtain salts with low to moderate diastereomeric excess values (Scheme [5]). For sulfide 27b, the major diastereomer was recrystallized and then hydrolyzed to provide sulfoxide 28b with 99% ee. The salt 29c, obtained with 57% de, was readily hydrolyzed to provide sulfoxide 28c with 56% ee.

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Scheme 5 Oxidation of sulfides to sulfoxides by Koser’s reagent

Chen and Xia prepared (hydroxy{[(+)10-camphorsulfonyl]oxy}iodo)benzene following Varvoglis’ procedure[31] and used it in the oxidation of sulfides (Scheme [6]).[22] Unfortunately, the observed enantioselectivities were really poor.

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Scheme 6 Oxidation of sulfides to sulfoxides by a camphorsulfonyl-substituted hypervalent iodine reagent

In 2000, Zhdankin et al. prepared a new family of chiral λ5-iodane reagents, the benzodiazole oxides 9.[32] Using these new reagents, methyl phenyl sulfide was oxidized into the corresponding sulfoxide with low enantioselectivities (Scheme [7]).

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Scheme 7 Oxidation of sulfides to sulfoxides by benzodiazole oxides

In 2006, the same research group prepared another family of chiral λ5-iodane reagents, with the chirality being based on the (S)-proline moiety, and a better, but still moderate, enantioselectivity was observed in the oxidation of methyl tolyl sulfide 27b (Scheme [8]).[33]

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Scheme 8 Oxidation of sulfides to sulfoxides by (S)-proline based chiral λ5-iodane reagents
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Scheme 9 Oxidation of sulfides to sulfoxides by chiral ester based λ5-iodane reagents

In 2010, Wirth and co-workers prepared a different type of chiral λ5-iodane reagent starting from 2-iodobenzoyl chloride.[34] These reagents were tested in the oxidation of methyl phenyl sulfide; however, when these chiral reagents were used, either 0% or undetermined enantioselectivities were obtained (Scheme [9]).


# 4

Oxidation of Alkenes

The asymmetric oxidation of alkenes is a very interesting method for the rapid preparation of polyfunctional chiral molecules. Sharpless asymmetric epoxidation and asymmetric dihydroxylation are the most relevant examples of this type of reaction.[35] [36] The first example of asymmetric oxidation of styrene using a chiral hypervalent iodine reagent was described by Wirth and Hirt in 1997.[23] Using three different reagents, they obtained either the bis(tosyloxy) compound 31 or the mono(tosyloxy) mono(hydroxy) compound 32 (Scheme [10,] 7a, 7b and 7c). They further functionalized this type of reagent and obtained one year later 31 with an ee up to 53%,[37] (Scheme [10,] 7d) and finally up to 65% in 2001 (Scheme [10,] 7e).[38]

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Scheme 10 First oxidation of styrene by a hypervalent iodine reagent

In 2011, Fujita et al. applied their hypervalent iodine reagents in the development of enantioselective Prévost and Woodward reactions.[39] Using two sets of conditions, they selectively obtained either the syn 34 or anti 35 products with enantioselectivities up to 96% in both cases (Scheme [11]).

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Scheme 11 Enantioselective Prévost and Woodward reactions

In 2004, Zhdankin and co-workers described the β-iodocarboxylation of alkenes (Scheme [12]).[40] They achieved no diastereoselectivity in this reaction, but they were able to separate both diastereomers of 38b by fractional crystallization to obtain two enantiopure products.

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Scheme 12 β-Iodocarboxylation of alkenes

Wirth and co-workers developed, in 2003, a new lactonization reaction. In this reaction, the hypervalent iodine reagent induced the formation of a phenonium ion leading finally to an aryl-migrated lactone (Scheme [13]).[41] Unfortunately, the use of a chiral reagent led to the expected product 40 in only 4% ee.

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Scheme 13 Lactonization with phenonium ion participation induced by a chiral hypervalent iodine reagent

In 2007, Fujita et al. developed the tetrahydrofuranylation of but-3-enyl carboxylates 41 using chiral hypervalent iodine reagents.[42] The expected furans 42 were obtained with up to 64% ee (Scheme [14]).

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Scheme 14 Enantioselective tetrahydrofuranylation of but-3-enyl carboxylates

In 2010, they used the same lactate-derived hypervalent iodine reagents in the endo-selective oxylactonization of 2-(alk-1-en-1-yl)benzoates 43.[43] The unexpected six-membered-ring lactones 44 were obtained with very high regio­selectivity and up to 97% ee (Scheme [15]). The authors suggested, from the observed syn selectivity, the mechanism described in Scheme [16] with a preference for the 43 → A → B → 44 pathway.

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Scheme 15 Enantioselective oxylactonization of ortho-alk-1-enylbenzoates
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Scheme 16 Plausible reaction mechanism for the enantioselective oxylactonization reaction

Fujita and co-workers then applied this method to the enantioselective synthesis of 4-hydroxymellein, fusarentin, monocerin derivatives (Figure [3]),[44] [45] and 4-hydroxyisochromanones.[46]

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Figure 3 Target molecules synthesized by Fujita and co-workers

More recently, the same research group developed a different strategy to obtain enantioenriched 4-hydroxymellein derivatives.[47] Starting from o-alkenylbenzamides 46, they performed a sequence of two oxidations: the first accomplished the asymmetric ring closure of 46 by their best chiral hypervalent iodine 11a to obtain compound 47, and the second involved the C–H activation at C8 catalyzed by the palladium salt, using a hypervalent iodine reagent as acetylating agent (Scheme [17]). 4-Hydroxymellein (45a) and its derivative 45d were both obtained with moderate overall yields and 90% ee.

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Scheme 17 Oxidation sequence on o-alkenylbenzamides by hypervalent iodine reagents to produce 4-hydroxymellein derivatives

In 2007, Wirth and co-workers developed the first chiral aziridination of alkenes using Murdoch’s precursor[48a] (51) and Imamoto’s reagent[19] (4′; Scheme [18]).[48b] However, the expected aziridine 50 was obtained in both cases with a low to moderate yield and very low enantiomeric excess.

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Scheme 18 First enantioselective aziridination of alkenes mediated by a chiral hypervalent iodine reagent

In 2011, Che, Xu and co-workers described the intramolecular aziridination of allylic carbamate using chiral hypervalent iodine reagent 51′.[49] After two steps, the expected product 54 was obtained in good yield and with complete diastereoselectivity, but the enantioselectivity remained low (Scheme [19]).

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Scheme 19 Enantioselective aziridination of allylic carbamates

In 2011, Muñiz and co-workers described the first intermolecular diamination reaction promoted by a chiral hypervalent iodine reagent.[50] The reaction proceeded very well on a whole range of styrene derivatives 55 with enantioselectivities up to 95% (Scheme [20]). From 56, the four methylsulfonyl groups could be removed, allowing for the synthesis of (S)-levamisole in a few steps as an example. In 2013, the authors investigated another reagent derived from binaphthyl and obtained 56 with up to 32% ee.[51]

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Scheme 20 Intermolecular enantioselective diamination of alkenes

In 2012, Wirth and Farid described the first efficient stereoselective oxyamination of alkenes using a chiral hypervalent iodine reagent.[52] The expected isourea was obtained with up to 99% ee in the stereoselective cyclization shown in Scheme [21].

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Scheme 21 Stereoselective oxyamination using a chiral hypervalent iodine reagent

The same research group recently developed new chiral hypervalent iodine catalysts for the intramolecular enantio­selective diamination of alkenes.[13] In this reaction, they obtained interesting bicyclic products 60 with enantioselectivities up to 94% by using a stoichiometric amount of reagent 20 (Scheme [22]). The reaction was also successful with the use of only 20 mol% of precursor with sodium perborate as the stoichiometric oxidant, and lower but still moderate enantioselectivities were obtained (up to 86% ee).

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Scheme 22 Enantioselective intramolecular diamination of alkenes

Lupton and co-workers achieved, in 2009, the enantioselective dibromination of alkenes using a chiral λ5-iodane reagent;[53] however, 62 was obtained with only poor enan­tioselectivity (Scheme [23]).

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Scheme 23 Enantioselective dibromination reaction

In 2011, Nicolaou et al. described the first enantioselective dichlorination reaction using an aryliodo dichloride as the chlorine source.[54] Various allylic alcohols were dichlorinated, with enantioselectivities up to 85% (Scheme [24]). The authors proposed a mechanism in which a chlorenium ion would transfer from an electrophilic chlorinating reagent generated through attack of the aryliodo dichloride by one of the quinuclidine nitrogens of the chiral catalyst (Figure [4]).

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Scheme 24 Enantioselective dichlorination reaction
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Figure 4 Proposed arrangement in the dichlorination reaction by Nicolaou et al.
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Scheme 25 Enantioselective aminofluorination reactions

In 2013, Nevado and co-workers described the first regio- and enantioselective aminofluorination reactions of alkenes induced by chiral aryliodo difluoride reagents.[55] The formation of six-membered rings in a regioselective manner proceeded well without any additive; however, the presence of a gold catalyst was necessary to obtain the seven-membered-ring compounds 68 (Scheme [25]). The corresponding intermolecular reaction between styrene derivatives and amines was investigated on styrene derivatives and was successful in its racemic version.

Recently Kita, Shibata and co-workers developed a catalytic version of the enantioselective aminofluorination reaction.[56] They employed 15 mol% of catalyst 51 using m-chloroperbenzoic acid as the stoichiometric oxidant and either­ hydrogen fluoride pyridine (nHF-Pyridine) or 46% aqueous hydrofluoric acid as the fluorine source, and they obtained the expected six-membered-ring compounds 66 from the corresponding γ-aminoalkenes 65 with up to 70% ee (Scheme [26]).

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Scheme 26 Enantioselective catalytic aminofluorination reactions

In 2013, Wirth and co-workers discovered a new stereoselective rearrangement mediated by a chiral hypervalent iodine reagent.[57] This method makes it possible to obtain α-arylated carbonyl compounds 70 with enantioselectivities up to 99% (Scheme [27]). The proposed mechanism for this reaction is described in Scheme [28]. Compound 69 reacts with hypervalent iodine reagent 11c leading to intermediate A, then phenonium ion B is formed, and finally the reaction of a second nucleophile leads to the expected product 70 (Scheme [28]).

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Scheme 27 Stereoselective rearrangement with a chiral hypervalent iodine reagent
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Scheme 28 Proposed mechanism for the transformation of 69 into 70 via a phenonium ion intermediate
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Scheme 29 Enantioselective oxidative aminations of allenes

Very recently, Muñiz and co-workers described the first oxidative amination reaction of allenes mediated by a chiral hypervalent iodine reagent.[58] Without any additive, they obtained the expected internal regioisomer 72 with a good yield, moderate diastereoselectivity and low enantiomeric excess (Scheme [29]). After addition of triphenylphosphine oxide, both the diastereoselectivity and the enantioselectivity improved, but the enantiomeric excess unfortunately remained low. They proposed a mechanism in which the hypervalent iodine reagent reacts on the allene to form a cationic intermediate, which itself then reacts with tosylimidate without efficient differentiation of its enantiotopic faces (Scheme [30]).

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Scheme 30 Proposed cationic intermediate in Muñiz’s system, explaining the low enantioselectivity

# 5

α-Functionalization of Carbonyl Compounds

Among the reactions induced by chiral hypervalent iodine reagents, the α-functionalization of carbonyl compounds is probably the most widely studied reaction.[59] [60] In pioneering work, Wirth and Hirt described for the first time in 1997 the enantioselective α-oxytosylation of propiophenone using a substoichiometric amount of chiral hypervalent iodine reagent, obtaining up to 15% enantiomeric excess (Scheme [31]).[23] They improved the enantioselectivity up to 28% ee one year later by modifying the structure of the chiral hypervalent iodine reagent slightly,[37] and up to 40% in 2001.[38] In 2007, this reaction was carried out in a catalytic version as mentioned in the introduction, using m-chloroperbenzoic acid as the stoichiometric oxidant; this transformation was the first example of a catalytic asymmetric oxidation by a chiral hypervalent iodine organocatalyst.[26] They synthesized and used many other catalysts and obtained up to 39% ee.[61] They also investigated the use of various hypervalent iodine organocatalysts in the lactonization reaction of 5-oxo-5-phenylpentanoic acid, but almost no enantioselectivity was observed in all cases.[62]

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Scheme 31 First enantioselective α-functionalization of a carbonyl compound by a hypervalent iodine reagent

In 2011, Zhang and co-workers synthesized various spirobiindane scaffold based iodoarenes 12 in order to investigate their activity in the enantioselective α-oxytosylation of ketones (Scheme [32]).[63] An enantioselectivity of up to 53% ee was obtained for the α-oxytosylation of propiophenone (23a).

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Scheme 32 α-Functionalization of carbonyl compounds by spirobiindane-based iodoarene catalysts

In 2012, Moran and Rodríguez synthesized several chiral iodoarenes and used them as catalysts for the enantioselective α-oxytosylation of propiophenone and the lactonization of 5-oxo-5-phenylpentanoic acid.[64] The best enan­tioselectivity they obtained for the first reaction was only 18% ee; however, an unprecedented enantiomeric excess of 51% was obtained for the second reaction (Scheme [33]).

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Scheme 33 α-Functionalization of a carbonyl compound by Moran’s catalysts

In 2012, Legault and Guibault studied the catalytic activity of hypervalent iodine catalysts when a sterically hindered functional group was placed ortho to the iodine (Scheme [34]).[65] They explained, using calculations, that this enhancement of the catalytic activity was due to torsion-induced destabilization, and they were able to show experimentally that, indeed, the presence of a functional group in the position ortho to the iodine had a dramatic effect on its reactivity (Scheme [34]).

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Scheme 34 Effect of an ortho substituent on the catalytic activity of the iodine

The same research group carried out a computational study of the reaction intermediate in their system and they found out that in the most electrophilic aryloxazoline iodane intermediate, it is the oxygen atom that binds to the iodine center (Figure [5]); consequently, the stereogenic center in the α-position relative to this oxygen atom has a significant effect on the catalytic activity in the oxidation reaction (Scheme [35]).[66] With this family of catalysts they obtained­ up to 54% ee in the α-oxytosylation of propiophenone, the best enantioselectivity obtained so far for this reaction.

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Figure 5 The most electrophilic iodane intermediate (calculated) in Legault­’s system
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Scheme 35 Effect of the oxazoline α-substituent on the catalytic activity of the iodine

They further functionalized their catalysts and showed that a quaternary center in the position α to the oxazoline oxygen prevented efficient facial discrimination on the iodonium intermediate (Scheme [36]).[67] These discoveries may lead to great improvements in Birman’s and Lupton’s systems (see Schemes 48 and 23).

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Scheme 36 Effect of the oxazoline quaternary α-substituent on the catalytic activity of the iodine

In 2013, Berthiol and co-workers developed 3,3′-diiodo-Binol-fused maleimides as a new family of hypervalent iodine organocatalysts.[68] These aryliodines, the first ones bearing the iodine in the C3 position of a binaphthyl structure, have proven to be efficient in the α-oxytosylation reaction of ketones (Scheme [37]).

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Scheme 37 α-Oxytosylation of propiophenone by 3,3′-diiodo-Binol-fused maleimides

In 2010, Ishihara et al. performed the enantioselective oxidative cycloetherification reactions of ketophenols 77 using chiral quaternary ammonium (hypo)iodite salts 16 as catalysts and hydrogen peroxide as the stoichiometric oxidant.[12] The expected 2-acyl-2,3-dihydrobenzofuran derivatives 78 were obtained with good yields and high enantioselectivities (Scheme [38]).

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Scheme 38 Highly enantioselective oxidative cycloetherifications of ketophenols

In 2014, Wirth and Mizar described the umpolung attack of a nucleophile on a silyl enol ether 79, mediated by a chiral hypervalent iodine reagent.[69] They introduced various nitrogen and oxygen groups in the α-position of the cyclic ketones and achieved moderate to high enantioselectivities (Scheme [39]).

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Scheme 39 Stereoselective reactions of cyclic silyl enol ethers introducing nitrogen and oxygen nucleophiles

Recently, Kita, Shibata and co-workers developed a catalytic enantioselective fluorination reaction of β-dicarbonyl compounds.[56] They employed the same conditions as for the aminofluorination reaction described in Scheme [26] and obtained the expected fluorinated products 82 with up to 56% ee (Scheme [40]).

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Scheme 40 α-Fluorination of β-dicarbonyl compounds

It is also possible to create, in an asymmetric manner, a carbon–carbon bond in the α-position of a carbonyl compound by means of a hypervalent iodine reagent. The first example was described by Ochiai et al. in 1999.[70] They prepared 1,1′-binaphthyl-2-yl(phenyl)iodonium tetrafluoroborate 8 and applied it in the α-phenylation of β-keto ester enolates 81 (Scheme [41]), obtaining the expected products with moderate enantioselectivities.

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Scheme 41 α-Phenylation of β-keto ester enolates

In 2013, Waser and co-workers achieved the enantioselective phase-transfer-catalyzed alkynylation of cyclic β-keto esters with hypervalent iodine reagents.[71] The expected products were obtained with moderate to excellent yields and up to 79% ee (Scheme [42]).

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Scheme 42 First enantioselective phase-transfer-catalyzed alkynylation of β-keto esters

In 2014, Maruoka and co-workers greatly improved the enantioselectivity of this phase-transfer-catalyzed alkynylation of cyclic β-keto esters, introducing a modification in the hypervalent iodine reagent (Scheme [43, 21b]).[72] Moreover the alkynylated products were directly cyclized using N-iodosuccinimide to obtain spiro-2(3H)-furanones (Scheme [43]). The authors suggested two plausible structures as intermediates in this reaction (Figure [6]).

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Scheme 43 Synthesis of spiro-2(3H)-furanones via enantioselective phase-transfer-catalyzed alkynylation
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Figure 6 Proposed plausible structures as intermediates in the reaction described in Scheme [43]

# 6

Dearomatization Reactions

In pioneering work, Siegel and Antony described the first oxidative dearomatization mediated by iodoarene di­acetates.[73] Since then, dearomatization reactions have been applied widely in organic synthesis, especially as key steps in the synthesis of complex natural products.[74] [75] The development of enantioselective versions of these reactions was essential.[76]

In 2008, Kita and co-workers reported the first example of the enantioselective intramolecular dearomatization of naphthols mediated by a hypervalent iodine reagent.[77] They developed both stoichiometric and catalytic versions of the reaction (Scheme [44]). They synthesized one year later a whole range of chiral spirobiindane hypervalent iodine catalysts in order to improve the catalytic system.[78]

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Scheme 44 First asymmetric dearomatizing spirolactonization of naphthols by a hypervalent iodine reagent

In 2013, they proposed a model in which R groups in the ortho positions relative to the iodines affected their chiral environment (Figure [7]); they were able to synthesize a range of chiral bis(ortho-subsituted)spirobiindanes in order to improve the enantioselectivity of the oxidation reactions.[79]

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Figure 7 Proposed model to show the influence of R groups on the chiral environment of the iodine in Kita’s system

They applied their best catalyst to the spirolactonization of various naphthol derivatives (Scheme [45]). Interestingly, they also successfully applied Ishihara’s catalyst 11e in this reaction and obtained a good enantioselectivity.

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Scheme 45 Extended scope of asymmetric dearomatizing spirolactonization of naphthols

In 2010, Ishihara and co-workers developed a broad range of C 2-symmetric iodoarenes and applied them in oxidative spirolactonization reactions.[80] Their catalysts comprised three units, A being the iodoaryl moiety, B being the chiral linkers and C being the subfunctional groups (Figure [8]). They especially modulated the C part, as the authors assumed that the chiral environment around the iodine center should be constructed whenever possible through two n–σ* interactions between the electron-deficient iodine(III) center and two carbonyl groups (11f, Figure [8]), or through two hydrogen-bonding interactions between the iodine(III) ligands and acidic hydrogens of C (11g, Figure [8]).

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Figure 8 Proposed model to show the influence of R groups on the chiral environment of iodine

They applied the best catalyst of the series to the reaction of different 1-naphthol derivatives and obtained the expected spirolactones with good yields and good enantio­selectivities (Scheme [46], top). The same year, but in another report, they showed that the use of an excess of m-chloroperbenzoic acid in this reaction led to the selective oxidation of the double bond into an epoxide.[81] The expected epoxyspirolactones 90a and 90b were obtained with a moderate diastereoselectivity and an excellent enantioselectivity for the major product (Scheme [46]).

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Scheme 46 Asymmetric dearomatizing spirolactonization of naphthols by Ishihara’s catalysts

In 2009, Quideau et al. developed the first enantioselective intermolecular hydroxylative phenol dearomatization catalyzed by iodoarene catalysts.[82] As in Ishihara’s case, the use of an excess of m-chloroperbenzoic acid allowed for the subsequent diastereoselective epoxidation of the remaining double bond to take place (Scheme [47]).

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Scheme 47 First asymmetric hydroxylative dearomatization of 2-methylnaphthol by hypervalent iodine catalysts

The same year, Birman and Boppisetti prepared the chiral 2-(o-iodoxy)oxazoline 14f and applied it in the oxidation of four dimethylphenol isomers.[83] This reaction produced o-quinol derivatives that cyclodimerized spontaneously via regio- and stereoselective intermolecular Diels–Alder reaction to give tricyclic compounds.[84] The expected products were obtained with moderate yields and enan­tioselectivities (Scheme [48]).

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Scheme 48 Hydroxylative dearomatization of dimethylphenols by a hypervalent iodine reagent

In 2013, Ishihara and co-workers used their chiral iodoarenes in the enantioselective oxidative dearomatization of phenols and the subsequent Diels–Alder reaction on the obtained diene intermediates.[85] Various alkenes were used and the expected cyclohexadienone spirolactones 101 were obtained with high to excellent enantioselectivities (Scheme [49]).

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Scheme 49 Asymmetric dearomatizing spirolactonization of phenols by Ishihara’s catalyst and subsequent Diels–Alder reaction

More recently, Quideau and co-workers synthesized various chiral binaphthylic and biphenylic iodanes and applied them in asymmetric hydroxylative phenol dearomatizations (Scheme [50]).[86] They obtained up to 73% ee for the hydroxylative oxidation of 2-methylnaphthol (91a). They also investigated this reaction on a series of 2-alkylphenols; these substrates led to o-quinol intermediates that readily cyclodimerized under the reaction conditions. The reaction with thymol (102) led to the expected dimer 103 in excellent yield and with an enantioselectivity of 94% ee (Scheme [50]).

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Scheme 50 Efficient asymmetric hydroxylative dearomatization of phenols

In 2013, Harned and Volp described the para-hydroxylative oxidation of phenols in the preparation of enantioenriched p-quinols.[87] They used molecular modeling to design a new chiral hypervalent phenyliodine catalyst and applied it in this reaction, obtaining the expected p-quinols 105 with moderate yields and enantioselectivities (Scheme [51]).

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Scheme 51 Enantioselective synthesis of p-quinols

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Conclusion

In this review, we have compiled an overview of the different enantioselective reactions that have been performed using hypervalent iodine reagents and catalysts. Thanks to the unique properties of iodine, great achievements have been accomplished in this field. However a lot of things remain to be accomplished in chiral hypervalent iodine chemistry. The enantioselectivities are generally still only moderate, in sulfide oxidations for example, and the design of new and more efficient reagents is necessary. The synthesis of recyclable chiral hypervalent iodine is also an important challenge because of the molecular weight and the cost of such reagents. In the reactions using catalytic amounts of chiral hypervalent iodine organocatalysts, the stoichiometric oxidant is in most cases m-chloroperbenzoic acid; however, this oxidant does not fit for all oxidation reactions and presents limitations with regard to the functionalities that can be borne by the substrate to be oxidized. The possibility of using molecular oxygen or hydrogen peroxide as the stoichiometric oxidant would be a major breakthrough in this field. Another limitation in the field of chiral hypervalent iodine chemistry is the lack of clear pieces of mechanistic evidence. In general, the described mechanistic pathways are only speculative, without any evidence on the real intermediates involved in such reactions; a lot of effort is still needed in order to bring important information to light.

In summary, hypervalent iodine chemistry is still in its infancy and we expect that much effort will be put forth in the near future in order to gain a better understanding of the mechanistic aspects in oxidation reactions. We also anticipate that new stereoselective oxidation reactions will be discovered and developed, and finally that these reagents will find broader applications in organic synthesis.


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Acknowledgment

Financial support from CNRS and Université Joseph Fourier is gratefully acknowledged.



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Figure 1 Hypervalent λ3- and λ5-iodane geometries and commercially available examples
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Figure 2 Different existing structures of hypervalent iodine reagents, catalysts or precursors
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Scheme 1 First oxidation reactions catalyzed by a hypervalent iodine organocatalyst by Ochiai et al. (a) and Kita et al. (b)
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Scheme 2 First asymmetric oxidation of sulfides to sulfoxides by a chiral hypervalent iodine reagent
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Scheme 3 Real form of the reagent obtained by reaction between iodosylbenzene and dibenzoyltartaric acid, and its use in the oxidation of sulfides to sulfoxides
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Scheme 4 First catalytic oxidation of sulfides to sulfoxides by a hypervalent iodine catalyst; CTAB = cetyltrimethylammonium bromide
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Scheme 5 Oxidation of sulfides to sulfoxides by Koser’s reagent
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Scheme 6 Oxidation of sulfides to sulfoxides by a camphorsulfonyl-substituted hypervalent iodine reagent
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Scheme 7 Oxidation of sulfides to sulfoxides by benzodiazole oxides
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Scheme 8 Oxidation of sulfides to sulfoxides by (S)-proline based chiral λ5-iodane reagents
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Scheme 9 Oxidation of sulfides to sulfoxides by chiral ester based λ5-iodane reagents
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Scheme 10 First oxidation of styrene by a hypervalent iodine reagent
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Scheme 11 Enantioselective Prévost and Woodward reactions
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Scheme 12 β-Iodocarboxylation of alkenes
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Scheme 13 Lactonization with phenonium ion participation induced by a chiral hypervalent iodine reagent
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Scheme 14 Enantioselective tetrahydrofuranylation of but-3-enyl carboxylates
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Scheme 15 Enantioselective oxylactonization of ortho-alk-1-enylbenzoates
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Scheme 16 Plausible reaction mechanism for the enantioselective oxylactonization reaction
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Figure 3 Target molecules synthesized by Fujita and co-workers
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Scheme 17 Oxidation sequence on o-alkenylbenzamides by hypervalent iodine reagents to produce 4-hydroxymellein derivatives
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Scheme 18 First enantioselective aziridination of alkenes mediated by a chiral hypervalent iodine reagent
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Scheme 19 Enantioselective aziridination of allylic carbamates
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Scheme 20 Intermolecular enantioselective diamination of alkenes
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Scheme 21 Stereoselective oxyamination using a chiral hypervalent iodine reagent
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Scheme 22 Enantioselective intramolecular diamination of alkenes
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Scheme 23 Enantioselective dibromination reaction
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Scheme 24 Enantioselective dichlorination reaction
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Figure 4 Proposed arrangement in the dichlorination reaction by Nicolaou et al.
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Scheme 25 Enantioselective aminofluorination reactions
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Scheme 26 Enantioselective catalytic aminofluorination reactions
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Scheme 27 Stereoselective rearrangement with a chiral hypervalent iodine reagent
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Scheme 28 Proposed mechanism for the transformation of 69 into 70 via a phenonium ion intermediate
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Scheme 29 Enantioselective oxidative aminations of allenes
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Scheme 30 Proposed cationic intermediate in Muñiz’s system, explaining the low enantioselectivity
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Scheme 31 First enantioselective α-functionalization of a carbonyl compound by a hypervalent iodine reagent
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Scheme 32 α-Functionalization of carbonyl compounds by spirobiindane-based iodoarene catalysts
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Scheme 33 α-Functionalization of a carbonyl compound by Moran’s catalysts
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Scheme 34 Effect of an ortho substituent on the catalytic activity of the iodine
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Figure 5 The most electrophilic iodane intermediate (calculated) in Legault­’s system
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Scheme 35 Effect of the oxazoline α-substituent on the catalytic activity of the iodine
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Scheme 36 Effect of the oxazoline quaternary α-substituent on the catalytic activity of the iodine
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Scheme 37 α-Oxytosylation of propiophenone by 3,3′-diiodo-Binol-fused maleimides
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Scheme 38 Highly enantioselective oxidative cycloetherifications of ketophenols
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Scheme 39 Stereoselective reactions of cyclic silyl enol ethers introducing nitrogen and oxygen nucleophiles
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Scheme 40 α-Fluorination of β-dicarbonyl compounds
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Scheme 41 α-Phenylation of β-keto ester enolates
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Scheme 42 First enantioselective phase-transfer-catalyzed alkynylation of β-keto esters
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Scheme 43 Synthesis of spiro-2(3H)-furanones via enantioselective phase-transfer-catalyzed alkynylation
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Figure 6 Proposed plausible structures as intermediates in the reaction described in Scheme [43]
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Scheme 44 First asymmetric dearomatizing spirolactonization of naphthols by a hypervalent iodine reagent
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Figure 7 Proposed model to show the influence of R groups on the chiral environment of the iodine in Kita’s system
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Scheme 45 Extended scope of asymmetric dearomatizing spirolactonization of naphthols
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Figure 8 Proposed model to show the influence of R groups on the chiral environment of iodine
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Scheme 46 Asymmetric dearomatizing spirolactonization of naphthols by Ishihara’s catalysts
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Scheme 47 First asymmetric hydroxylative dearomatization of 2-methylnaphthol by hypervalent iodine catalysts
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Scheme 48 Hydroxylative dearomatization of dimethylphenols by a hypervalent iodine reagent
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Scheme 49 Asymmetric dearomatizing spirolactonization of phenols by Ishihara’s catalyst and subsequent Diels–Alder reaction
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Scheme 50 Efficient asymmetric hydroxylative dearomatization of phenols
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Scheme 51 Enantioselective synthesis of p-quinols