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Synthesis 2011(4): 517-538  
DOI: 10.1055/s-0030-1258328
REVIEW
© Georg Thieme Verlag Stuttgart ˙ New York

α-Functionalization of Carbonyl Compounds Using Hypervalent Iodine Reagents

Eleanor A. Merritt, Berit Olofsson*
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, 106 91 Stockholm, Sweden
Fax: +46(8)154908; e-Mail: berit@organ.su.se;

Further Information

Publication History

Received 19 September 2010
Publication Date:
15 November 2010 (online)

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Biographical Sketches

Eleanor A. Merritt, born in the UK in 1982, obtained her MChem degree from Cardiff University in 2004. She then began postgraduate studies in the research group of Dr. Mark C. Bagley at Cardiff University, where she worked on the synthesis of thiopeptide antibiotics. Since obtaining her PhD in 2008, she has commenced postdoctoral research at Stockholm University under the direction of Assoc. Prof. Berit Olofsson where she is working on the development of environmentally benign methodology within hypervalent iodine chemistry.
Berit Olofsson was born in 1972 in Sundsvall, Sweden. She obtained her MSc in 1998 from Lund University, and finished her PhD in asymmetric synthesis at KTH, Stockholm (with P. Somfai) in 2002. She then moved to Bristol University, UK for a postdoc in the field of methodology and natural product synthesis with V. K. Aggarwal. Returning to Sweden, she became assistant supervisor at Stockholm University in the group of J.-E. Bäckvall. In 2006 she was appointed to Assistant Professor, and was recently appointed to a permanent position as Associate Professor. Her research interests include the synthesis and application of hypervalent iodine compounds in asymmetric synthesis.

Abstract

α-Functionalized carbonyl compounds are versatile intermediates in organic synthesis. A broad range of both carbon and heteroatom substituents can be introduced into the α-position of carbonyl compounds using hypervalent iodine reagents. Herein we summarize the use of these environmentally benign reagents with particular emphasis on catalytic and asymmetric methodology developed over the past decade.

1 Introduction

2 Oxygenation

3 Halogenation

4 Trifluoromethylation

5 Arylation

6 Alkynylation and Alkenylation

7 Homocoupling

8 Functionalization of α,β-Unsaturated Carbonyl Compounds

9 Miscellaneous

10 Summary

Key words

catalysis - asymmetric synthesis - oxidation - hypervalent iodine - C-C bond formation

1  Introduction

α-Functionalized carbonyl compounds are versatile intermediates for the synthesis of a variety of heterocyclic compounds of medicinal interest, as well as natural products and related compounds. Many fields of organic chemistry provide elegant solutions to the challenges of α-functionalization of carbonyl compounds. In recent years, organocatalysis has become a versatile tool in this area, enabling the incorporation of a vast range of carbon and heteroatom electrophiles in an asymmetric fashion. [¹] Despite the success of organocatalysis in α-heterofunctionalization, α-arylation of carbonyl compounds is dominated by transition-metal catalysis. [²]

Hypervalent iodine compounds have recently received considerable attention as mild, non-toxic and selective reagents in organic synthesis. [³] They are efficient alternatives to toxic heavy-metal-based oxidants and expensive organometallic catalysts in many organic transformations. Several comprehensive reviews [4] and books [5] have been published on the topic of hypervalent iodine chemistry.

Iodine(V) reagents, such as Dess-Martin periodinane (DMP) and 2-iodoxybenzoic acid (IBX), are frequently used as mild oxidants of alcohol moieties in total syntheses of natural products. IBX can also effect oxidative transformations of a variety of other functional groups. [6] Iodine(III) compounds with two heteroatom ligands, such as (diacetoxyiodo)benzene (PIDA), [bis(trifluoroacetoxy)]iodobenzene (PIFA) and iodosylbenzene, are employed in oxidations of alcohols and alkenes, as well as in α-functionalization of carbonyl compounds. [³] Figure  [¹] illustrates some of the common hypervalent iodine reagents that will be referred to throughout this review article. For the preparation of these reagents, the reader is directed to reviews on that topic. [4]

Figure 1 Commonly used hypervalent iodine reagents

Iodine(III) reagents with two carbon ligands have also been widely used in the α-functionalization of carbonyl compounds. Diaryliodonium salts are the best known compounds in this class. Due to their highly electron-deficient­ nature and superior leaving group ability, they serve as versatile electrophilic arylating agents with a variety of nucleophiles. [7]

Alkynyl(aryl)iodonium salts display somewhat similar properties, although the comparative lack of facile synthetic routes to this class of compounds has limited their use in synthetic chemistry. [8]

Recent progress in hypervalent iodine chemistry has involved the development of catalytic systems, thereby obviating the stoichiometric amount of iodoarene generally formed as a byproduct in these reactions. [³b] [9] After more than a decade of research into asymmetric reactions with hypervalent iodine reagents, a number of highly enantio­selective reactions have recently been developed. [¹0] With these breakthroughs in mind, hypervalent iodine compounds show great potential as environmentally benign and selective reagents in many transformations that are yet undiscovered.

This review provides an overview of the use of hypervalent iodine reagents to α-functionalize carbonyl compounds, with a focus on recent improvements, catalytic and asymmetric reactions. Moriarty and Prakash reviewed this topic in 1995 and 1999; [¹¹] since then, the area has been covered only in general reviews on hypervalent iodine chemistry.

The article is divided into sections according to the group being introduced into the α-position, and each section is ordered with the catalytic and asymmetric variants of the transformation at the end. Reactions that deliver α-substituted carbonyl compounds from starting materials that do not contain this functional group are generally not covered. However, the use of silyl enol ethers is included in sections containing only few reports using carbonyl compounds. Likewise, reactions where the carbonyl group is present in the hypervalent iodine reagent, for example in iodonium ylides, are outside the scope of this review. Oxidative dearomatization of phenols, which can be considered as a special type of α-functionalization, has recently been reviewed and is therefore omitted. [¹²]

2 Oxygenation

The α-hydroxycarbonyl group is of interest to synthetic chemists owing to its ubiquity in nature, occurring in polyketide, terpenoid and alkaloid natural products. The most widely used direct approach to α-oxycarbonyl compounds is via oxidation of an enolate, although metal-free organocatalytic methods are becoming more widespread. [¹³] [¹4] Hypervalent iodine reagents provide a route to a range of α-oxygenated carbonyl compounds, obviating the need for anhydrous and anaerobic reaction conditions used in enolate reactions. Herein we discuss the major developments in hypervalent iodine mediated α-oxygenation chemistry from its inception in the late 1970s to present-day development of catalytic and asymmetric variants of these transformations.

2.1 Sulfonyloxylation

2.1.1 α-Sulfonyloxylation Using HTIB and Related Reagents

The most numerous examples of α-oxygenations of carbonyl compounds are tosyloxylation reactions using [hydroxy(tosyloxy)iodo]benzene (HTIB). First prepared in 1970 by Neilands and Karele, [¹5] this versatile reagent was studied in detail by Koser and co-workers and is thus frequently referred to as Koser’s reagent. [¹6] Indeed, Koser et al. were first to report the use of HTIB as an α-oxytosylating agent (Scheme  [¹] ). [¹7]

Scheme 1 Koser’s α-tosyloxylation of ketones using HTIB

This work was subsequently extended by Lodaya and Koser­ to include α-mesyloxylation of ketones using [hydroxy(mesyloxy)iodo]benzene (HMIB). [¹8] In 1990, Varvoglis et al. successfully prepared {hydroxy[(+)-10-camphorsulfonyloxy]iodo}benzene and used this reagent in the α-(10-camphorsulfonyl)oxylation of a range of substrates including ketones, β-dicarbonyls and other carbonyls bearing an activated methylene group (Scheme  [²] ). [¹9]

Scheme 2 α-(10-Camphorsulfonyl)oxylation of carbonyls

Over the years there have been many developments and modifications of the reaction, such as solvent-free α-sulfonyloxylation of ketones by grinding HTIB with a ketone using a pestle and mortar, [²0] and use of ultrasound. [²¹] Nabana­ and Togo investigated the use of a range of [hydroxy(tosyloxy)iodo]arenes and [hydroxy(phosphoryl­oxy)iodo]arenes in the α-tosyloxylation and α-phos­-phoryloxylation of ketones, respectively (Scheme  [³] ). [²²] It was found that the incorporation of trifluoromethyl substituents meta to the iodine greatly enhanced the reactivity over that of the parent reagents.

Scheme 3 Novel [hydroxy(tosyloxy)iodo]arenes used by Nabana and Togo

Lee and co-workers developed a rapid microwave-assisted method for the preparation of α-sulfonyloxylated carbonyl­ compounds using [hydroxy(2,4-dinitrobenzenesulfonyloxy)iodo]benzene. [²³] This methodology was subsequently extended to provide a route to α-hydroxy ketones by forming [hydroxy(2,4-dinitrobenzenesulfonyl­oxy)iodo]benzene in situ from PIDA and 2,4-dinitrobenzenesulfonic acid using water as the solvent (Scheme  [4] ). [²4] A similar method had been reported previously by Xie and Chen in which Koser’s reagent was used in place of the more electron-deficient nitro-substituted reagent. [²5]

Scheme 4 2,4-Dinitrobenzenesulfonic acid in α-oxygenation of ketones; DNs = 2,4-dinitrobenzenesulfonyl

A recent application of the α-tosyloxylation reaction using Koser’s reagent was reported in 2009 by Karade et al. in which the addition of sodium sulfide nonahydrate to the reaction mixture resulted in the formation of symmetrical keto disulfides (Scheme  [5] ). [²6]

Scheme 5 Synthesis of symmetrical keto disulfides from enolizable ketones

2.1.2 In situ Formation of HTIB

In situ formation of HTIB from various precursors is an increasingly common strategy in the preparation of α-tosyloxycarbonyl compounds. Tanaka and Togo recently reported an iodine(III)-mediated α-tosyloxylation of ketones in which a stoichiometric amount of 4-iodotoluene was oxidized using Oxone® in the presence of p-toluenesulfonic acid (Scheme  [6] ). [²7]

Scheme 6 4-Iodotoluene-mediated α-tosyloxylation of ketones

More widespread is the use of iodine(III) precursors to HTIB, such as PIDA, 4-iodotoluene difluoride (TolIF2), and iodosylbenzene. A solvent-free method for α-sulfonyl­oxylation of ketones was reported by Yusubov and Wirth in 2005 in which PIDA, a sulfonic acid and a ketone were ground together using a pestle and mortar. [²8] A microwave-assisted variant of this procedure has also been reported. [²9]

Zhang and co-workers recently published a detailed study on the α-oxygenation of β-dicarbonyls mediated by TolIF2 using a range of oxygen-containing nucleophiles, including p-toluenesulfonic acid, methanesulfonic acid, acetic acid, diphenyl phosphate, methanol, ethanol and isopropyl alcohol. [³0] A ligand-exchange mechanism to form the necessary iodine(III) species in situ was postulated (Scheme  [7] ) and was supported by NMR evidence. It is noteworthy that in most cases, these reactions proceeded at room temperature in dichloromethane, as opposed to the standard conditions of reflux in acetonitrile.

Scheme 7 α-Oxygenation using TolIF2

Iodosylbenzene was used by Togo and co-workers as the HTIB precursor for both α-tosyloxylation of ketones and oxidative α-tosyloxylation of alcohols (Scheme  [8] ). [³¹]

Scheme 8 Use of iodosylbenzene in α-tosyloxylation reactions

Wirth and co-workers have reported the use of iodoxolone-based hypervalent iodine reagents in a number of transformations, including the preparation of α-tosyloxy ketones. [³²] Novel fluorinated iodoxolones were demonstrated to enhance the rate of tosyloxylation reactions amongst others (Scheme  [9] ). [³³]

Scheme 9 Wirth’s use of iodoxolone-based reagents

Karade et al. prepared an iodoxolone reagent similar to those used above by reacting DMP and p-toluenesulfonic acid. The resulting product 1 was found to be an efficient α-oxytosylating agent (Scheme  [¹0] ). [³4]

Scheme 10 Karade’s DMP-derived α-tosyloxylation reagent

Scheme 11 Iodine(V) in α-sulfonyloxylation reactions

Although almost exclusively the domain of iodine(III) reagents, there are some examples of iodine(V) and even iodine(VII) reagents in α-tosyloxylation of carbonyl compounds. Mahajan and Akamanchi reported the use of reagents such as DMP, IBX, HIO3 and HIO4 in conjunction with p-toluenesulfonic acid or methanesulfonic acid. DMP was found to be most effective under the conditions shown in Scheme  [¹¹] . [³5]

2.1.3 Recyclable Reagents

Over the past decade, several studies have been conducted in which various polymer-bound or other recyclable forms of hypervalent iodine reagents were used in the preparation of α-tosyloxy ketones. In 2001, Togo and co-workers investigated the α-tosyloxylation of ketones using two poly[4-hydroxy(tosyloxy)iodo]styrenes. [³6] Both reagents were able to α-oxytosylate ketones, in some cases­ more efficiently than HTIB (Scheme  [¹²] ). These reagents can also be employed in the oxidative α-tosyloxylation of alcohols, forming α-tosyloxy ketones directly. [³7]

Scheme 12 Polymer-bound HTIBs: PS = polystyrene, average molecular weight 45,000; PMS = poly(α-methylstyrene), average molecular weight 6,200

Nicolaou et al. prepared another polymer-bound variant of HTIB by treating a polystyrenesulfonic acid resin with PIDA­. This enabled the preparation of resins loaded with α-sulfonyloxy ketones, which could subsequently be used to generate heterocycle and enediyne libraries (Scheme  [¹³] ). [³8]

Scheme 13 Polystyrenesulfonic acid resin-based HTIB derivative

Many recyclable HTIB-type reagents have been developed in recent years, examples of which are illustrated in Figure  [²] . An adamantane-based PIDA reagent was reported by Kita and co-workers in 2004. [³9] This reagent could be readily converted into an HTIB derivative (Figure  [²] ) by reaction with p-toluenesulfonic acid, and then used in the tosyloxylation of propiophenone. The aryl iodide could be recovered almost quantitatively. Recyclable tetraphenylmethane-based reagents were subsequently developed by the same research group, and also proved useful in the α-sulfonyloxylation of ketones. [40] Biphenyl and terphenyl-based HTIB reagents were reported by Moroda and Togo in 2006. [4¹] These reagents demonstrated comparable reactivity to 4-(diacetoxyiodo)toluene and 4-[(hydroxy)(tosyloxy)iodo]toluene, but with the benefit of being easily recovered by filtration of the reaction mixture.

Figure 2 Recyclable HTIB reagents used in α-tosyloxylation reactions

In 2005, Handy and Okello prepared an ionic liquid variant of Koser’s reagent that was successfully employed in the α-tosyloxylation of ketones (Scheme  [¹4] ). [4²]

Scheme 14 Ionic liquid supported Koser’s reagent

2.1.4 Catalytic and/or Asymmetric Reactions

In recent years, the focus of research in this area has shifted towards the development of catalytic protocols for the preparation of α-tosyloxy ketones. Particularly prominent is the research conducted by Togo and Yamamoto, who in 2006 developed an iodobenzene-catalyzed α-tosyloxylation reaction using m-chloroperoxybenzoic acid as the stoichiometric oxidant (Scheme  [¹5] ). [4³]

Scheme 15 Iodobenzene-catalyzed α-tosyloxylation

The scope of this work was later extended to include polymer-supported iodobenzene, and to enable the preparation of α-tosyloxy ketones directly from alcohols, [44] as well as ionic liquid supported iodobenzene. [45]

The development of an asymmetric variant of the iodine(III)-mediated α-tosyloxylation reaction has been ongoing for more than a decade. In 1997, Wirth and Hirt published the synthesis of several chiral HTIBs, together with the first application of such reagents in the asymmetric α-tosyloxyation of ketones (Scheme  [¹6] , compounds 2 and 3). [46]

Scheme 16 Asymmetric α-tosyloxylation of propiophenone

Optimization of the chiral reagents by varying the substituents on the aromatic ring led to ee values of up to 28% (Scheme  [¹6] , compounds 4-6). [47] Further investigations showed that increased steric bulk of the ortho substituent improved the enantioselectivity. Compound 7, bearing an ethyl substituent in the ortho position, furnished α-tosylpropiophenone in 40% ee. [48] In 2007, a catalytic asymmetric version of this reaction was reported using 10 mol% enantiopure iodoarene in conjunction with m-chloroperoxybenzoic acid as the stoichiometric oxidant (Scheme  [¹7] ). [49] With compound 7 as the catalytically active species, the product was obtained in 59% yield and 27% ee as the R-enantiomer.

Scheme 17 Catalytic asymmetric α-sulfonyloxylation of ketones

It was proposed that path B operates in this reaction, as in path A, the stereocenter is distant from the α-carbon, thus enantio-induction would be unlikely. The use of enantiomerically pure esters as catalysts for this process was also investigated with menthyl and fenchyl esters proving most successful (compounds 8 and 9 respectively; Figure  [³] ), giving ee values of up to 39%. [50] [5¹]

Figure 3 Enantiomerically pure esters used in the asymmetric α-tosyloxylation of propiophenone

2.2 Hydroxylation

As with the α-tosyloxylation of ketones, the α-hydroxylation of carbonyl compounds using hypervalent iodine reagents has been known for a considerable length of time. Indeed, the first reported direct α-hydroxylation of ketones was published by Moriarty et al. in 1981 (Scheme  [¹8] ). [5²]

Scheme 18 α-Hydroxylation of ketones using iodosylbenzene

In the same year, Moriarty and Hu reported a PIDA-mediated conversion of carboxylate esters into either α-hydroxycarboxylic acids or α-alkoxy esters, with the product depending on choice of solvent and base (Scheme  [¹9] ). [5³] A multigram-scale variant of this reaction was also devised using 2-iodosylbenzoic acid. [54]

Scheme 19 Preparation of α-hydroxycarboxylic acids or α-alkoxy esters from esters using PIDA

In a departure from the more common use of basic reaction conditions, Moriarty subsequently developed a protocol for the α-hydroxylation of ketones under acidic conditions using PIFA and trifluoroacetic acid in acetonitrile-water (Scheme  [²0] ). [55]

Scheme 20 α-Hydroxylation of ketones under acidic conditions

For a more comprehensive discussion of the numerous significant contributions made to this field by Moriarty’s group, including α-hydroxylation of acetals, which falls outside the scope of this article, the reader is referred to the 2005 review article. [56]

Polymer-supported hypervalent iodine reagents have also found application in the α-hydroxylation of ketones. Togo et al. reported a method similar to Moriarty’s PIDA-mediated hydroxylation reaction using poly[4-(diacetoxyiodo)styrene] under basic conditions. [57] The same reagent was also used by Ley and co-workers under acidic conditions to prepare α-hydroxy ketones from aromatic ketones in quantitative yields (Scheme  [²¹] ). [58]

Scheme 21 Polymer-supported PIDA in the synthesis of α-hydroxy ketones

Kirsch successfully utilized IBX in the synthesis of α-hydroxy ketones from α-alkynyl carbonyl compounds (Scheme  [²²] ). [59] This unusual iodine(V)-mediated reaction was investigated further, and the substrate scope was expanded to include β-keto esters, β-keto amides and β-keto thioamides. [60]

Scheme 22 Examples of IBX-mediated α-hydroxylation reactions

In 2008, Huang and co-workers published an iodobenzene-catalyzed protocol for the preparation of aromatic α-hydroxy ketones using Oxone® as the stoichiometric oxidant. A diverse range of α-hydroxy ketones were prepared in moderate to good yields (Scheme  [²³] ). [6¹]

Scheme 23 Iodobenzene-catalyzed α-hydroxylation of ketones

To date, only one catalytic asymmetric α-hydroxylation using hypervalent iodine has been published. [6²] Using l-proline as catalyst and iodosylbenzene as oxidant, α-hydroxy ketones were prepared with ee values of up to 77% (Scheme  [²4] ).

Scheme 24 Organocatalytic asymmetric α-hydroxylation of ke­tones

2.3 Acyloxylation

α-Acetoxylation of ketones is the oldest of the hypervalent iodine mediated α-oxygenation reactions. It is also one of the least reported α-oxygenations, with tosyloxylations and hydroxylations being far more numerous. In 1978, Mizukami et al. reported the α-acetoxylation of acetophenones and β-diketones using PIDA (Scheme  [²5] ). [6³]

Scheme 25 Acetoxylation of acetophenones using PIDA

Some years later, Podoleov reported a similar method, in which a 9:1 mixture of acetic acid and water was used as solvent, and the sulfuric acid catalyst omitted. [64]

Two decades after Podoleov’s publication, Ochiai and co-workers reported an iodobenzene-catalyzed α-acetoxylation of ketones using m-chloroperoxybenzoic acid and boron trifluoride-diethyl ether complex. [9a] The proposed catalytic cycle is illustrated in Scheme  [²6] . A noteworthy feature of this protocol is that it is not limited to the use of acetophenones.

Scheme 26 Ochiai’s iodobenzene-catalyzed α-acetoxylation of ketones

Huang and co-workers subsequently reported a similar protocol in which 30% aqueous hydrogen peroxide and acetic anhydride were used to generate PIDA in situ. [65] Recently, a protocol for the formyloxylation of ketones was reported. [66] Initial α-tosyloxylation using HTIB was followed by reaction with N,N-dimethylformamide, then subsequent hydrolysis of the resulting iminium ion to yield the product (Scheme  [²7] ). Dimethylacetamide could be used in place of dimethylformamide to prepare α-acetoxy ketones.

Scheme 27 α-Acyloxylation of ketones

2.4 Other α-Oxygenations

In addition to the α-oxygenation categories discussed above, there are a number of reports on the use of other oxygen nucleophiles. α-Phosphorylation of ketones was reported by Koser et al. using (hydroxy{[bis(phenyl­oxy)phosphoryl]oxy}iodo)benzene, prepared by reaction of PIDA with diphenyl hydrogen phosphate (Scheme  [²8] ). [67] Moriarty prepared similar reagents for the α-methylphosphonylation of ketones, as well as for α-diphenyl- and α-dimethylphosphinylation reactions. [68]

Scheme 28 α-Phosphorylation of ketones

Liang and co-workers used IBX in the presence of potassium iodide in order to prepare a range of α-(2-iodobenzoyloxy)ketones (Scheme  [²9] ). [69]

Scheme 29 Synthesis of α-(2-iodobenzoyloxy)ketones

Moriarty used iodosylbenzene in conjunction with boron trifluoride-diethyl ether complex to perform a range of different α-functionalizations of β-diketones and β-keto esters, including α-mesyloxylation and alkoxylation. [70]

2.5 Intramolecular α-Oxygenations

Iodine(III) reagents have found numerous applications in the synthesis of lactones and many other oxygen-containing heterocycles. A review from 1994 covers the earlier developments in this field, [7¹] while other aspects of hypervalent iodine mediated cyclization reactions were reviewed in 2004. [7²] The examples presented herein are predominantly, although not entirely, drawn from more recent literature.

A common approach to the preparation of oxygen-containing heterocycles using iodine(III) reagents involves the initial formation of an α-tosyloxy ketone. Subsequent intramolecular attack of an oxygen nucleophile gives the product, as exemplified by the aroylcoumaranone synthesis shown in Scheme  [³0] . [7³]

Scheme 30 Synthesis of aroylcoumaranones

Alternatively, reaction with a nucleophile such as potassium methyl malonate followed by cyclization provides furanones (Scheme  [³¹] ). [74]

Scheme 31 Synthesis of arylfuranones

Murphy and West demonstrated the use of iodonium ylides, formed in situ from PIDA, in the synthesis of furanones under rhodium catalysis. [75] In this reaction, the iodonium ylide behaves as a diazo ketone surrogate, permitting direct conversion of activated methylene-containing compounds into the corresponding 2-substituted heterocycles (Scheme  [³²] ).

Scheme 32 Synthesis of furanones via iodonium ylides

The HTIB-mediated synthesis of keto γ-lactones from 5-keto acids was reported by Moriarty et al. in 1990. This reaction proved applicable to a wide range of substrates, some of which are highlighted in Scheme  [³³] . [76]

Scheme 33 Preparation of lactones from 5-keto acids

Recently an iodobenzene-catalyzed version of this transformation was reported by Ishihara and co-workers. [77] based on Ochiai’s α-acetoxylation protocol. [9a] HTIB was formed in situ from iodobenzene and p-toluenesulfonic acid, with m-chloroperoxybenzoic acid as the oxidant (Scheme  [³4] ). HTIB reacts with the enol to form intermediate 10, which is in equilibrium with iodonium carboxylate 11 and/or iodonium tosylate 12. Reductive elimination from 10, or SN2 substitution on 11 or 12, then affords the product, together with the iodoarene catalyst.

Scheme 34 Iodobenzene-catalyzed lactonization reaction

Wirth and co-workers recently reported a catalytic lactonization using chiral iodoarenes under similar conditions. The products were obtained in moderate yields with <5% ee, indicating that no tosyloxylated intermediate was formed and the products were instead formed via a substrate-iodoarene complex. [5¹]

Scheme 35 Synthesis of fused dihydrofurans (a) and proposed mechanism for the [1,5]-oxidative cyclization of Michael adducts (b)

Fused dihydrofurans can be prepared from tricarbonyl precursors using iodosylbenzene as shown in Scheme  [³5] (a). [78] Using this [1,5]-oxidative cyclization, a structurally diverse range of dihydrofurans was produced in up to 90% yield and with high diastereoselectivity. The proposed mechanism for the above reaction is illustrated in Scheme  [³5] (b). [78]

The use of hypervalent iodine reagents in synthetic chemistry in general, and α-oxygenation in particular, has become increasingly widespread in recent years. These environmentally benign reagents are now prevalent in areas­ traditionally dominated by metal-based reagents.

3 Halogenation

Standard reagents for halogenation reactions are often aggressive, unstable, toxic and corrosive. The introduction of hypervalent iodine reagents has enabled mild reaction conditions, selective reactions and nontoxic waste. Recent progress includes the use of recyclable reagents, which further reduce the environmental impact. The following section describes halogenations of saturated carbonyl compounds, whereas halogenations of unsaturated carbonyl compounds are discussed in section 8.4.

3.1 Fluorination

4-(Difluoroiodo)toluene (TolIF2) is an efficient α-fluorination reagent for several types of carbonyl compounds. Hara and co-workers have shown that this reagent fluorinates various β-dicarbonyl compounds in the presence of HF-amine complex. [79] The reagent can also be formed electrochemically in Et3N-5HF. [80] The same research group recently reported a modified procedure that gave monofluorinated products without added HF-amine (Scheme  [³6] ). This reaction was slower, but proceeded under neutral conditions to yield α-fluorinated β-keto esters, β-keto amides and diketones. [8¹]

Scheme 36 Monofluorination under neutral conditions

Direct fluorination of simple ketones cannot be performed with hypervalent iodine reagents, but α-fluoro ketones can be obtained by fluorination of the corresponding silyl enol ether. [8²]

Motherwell and co-workers have developed an α-fluorination of α-thiophenyl esters [8³] and amides. [84] The reaction proceeds in good yields via a fluoro-Pummerer mechanism (Scheme  [³7] ). Addition of more reagent leads to α,α-difluorinated product (2 equiv) and oxidation to the corresponding sulfoxide (3 equiv).

Scheme 37 Fluoro-Pummerer reaction

In a similar fashion, α-seleno esters and amides can be fluorinated­ in moderate yields. [85]

3.2 Chlorination

Similar to the fluorinations discussed above, α-chlorination of carbonyl compounds can be performed using 4-(dichloroiodo)arenes. Ketones and β-diketones were selectively monochlorinated in high yield with (dichloro­iodo)benzene under photochemical conditions in benzene. [86]

α-Chlorinated phosphonium salts can be prepared by reaction of phosphonium ylides with (dichloroiodo)benzene. Subsequent hydrolysis delivered the α-chlorinated ketones (Scheme  [³8] ). [87]

Scheme 38 Chlorination of phosphonium ylides

Togni and co-workers developed a catalytic asymmetric α-chlorination of β-keto esters using 4-(dichloroiodo)toluene and titanium complex 14, which delivered the products in moderate to good yields and enantioselectivities (Scheme  [³9] ). [88]

Scheme 39 Asymmetric α-chlorination (1-Nph = naphthalen-1-yl)

Fluorous aryl and alkyl iodine(III) chlorides have recently been used as chlorinating agents, with the added benefit of easy recovery and reuse of the resulting iodine(I) compound. Monochlorination was selectively obtained with dibenzoylmethane, whereas reaction with acetophenone resulted in a mixture of mono- and dichlorination. [89]

In 2009, Ibrahim and co-workers reported a rapid PIDA-mediated chlorination of 1,3-dicarbonyl compounds using substoichiometric amounts of titanium(IV) chloride as the chloride source (Scheme  [40] ). [90] Diketones, β-keto esters, β-keto amides and β-keto phosphonates could be employed in good to excellent yields.

Scheme 40 Chlorination of dicarbonyl compounds with PIDA

Treatment of the carbonyl compound with titanium(IV) chloride results in a titanium-enolate complex with concomitant release of a chloride ion, which is oxidized in situ by PIDA to an electrophilic chloronium ion equivalent, resulting in a net umpolung of the halide reactivity (Scheme  [4¹] ). [90]

Scheme 41 Umpolung strategy for chlorination

For a sequential chlorination procedure, see the following section.

3.3 Bromination and Iodination

Bromination of 1,3-dicarbonyl compounds can be performed by treatment with PIDA in a reaction analogous to that described in the chlorination section (vide supra). Using titanium(IV) bromide, the reaction is extremely fast and gives excellent yields for diketones, β-keto esters, β-keto amides and β-keto phosphonates (Scheme  [4²] ). [90]

Scheme 42 Bromination of dicarbonyl compounds with PIDA

Lee et al. showed that ketones can be α-iodinated by sequential treatment with [hydroxy(p-nitrobenzenesulfonyl­oxy)iodo]benzene (HNIB), forming an α-sulfonyloxy intermediate (see section 2.1) followed by potassium iodide or samarium(II) iodide (Scheme  [4³] ). [9¹] Replacement of HNIB with HTIB resulted in reduced yields. The two iodination methods gave similar results in all cases other than that of cyclic ketones, which were more efficiently iodinated with samarium(II) iodide.

Scheme 43 Sequential iodination of ketones

The same research group later developed a general α-halogenation protocol with HTIB followed by reaction with magnesium halides under solvent-free microwave irradiation conditions (Scheme  [44] ). [9²] This method halogenated ketones, β-keto esters and malonates in short reaction times and high yields.

Scheme 44 Sequential halogenation of ketones

4 Trifluoromethylation

The trifluoromethyl group is often present in synthetic drugs and agrochemicals, as it can favorably alter uptake, metabolism and mode of action. Synthetic strategies to incorporate the trifluoromethyl group include nucleophilic, electrophilic and radical methods. [9³]

Togni and co-workers recently developed the electrophilic, hypervalent iodine based trifluoromethylation reagents 15 and 16; the latter has become known as Togni’s reagent (Figure  [4] ). [94]

Figure 4 Togni’s trifluoromethylation reagents

Compound 16 reacted with β-keto esters under basic phase-transfer catalysis (PTC) conditions to deliver α-trifluoromethyl-substituted products (Scheme  [45] ). Cyclic β-keto esters were good substrates in this transformation, whereas the less reactive, acyclic substrates gave no product.

Scheme 45 Trifluoromethylation of β-keto esters (NMR yields)

α-Nitro esters could be trifluoromethylated in the presence of a catalytic amount of copper(I) chloride, thereby providing a route to the corresponding α-trifluoromethyl-α-amino acids (Scheme  [46] ). [95]

Scheme 46 Trifluoromethylation and reduction to α-amino acid (NMR yields)

Furthermore, reagents 15 and 16 have been used in trifluoromethylation of silyl enol ethers and silyl ketene acetals at elevated temperature, delivering the corresponding α-trifluoromethylated carbonyl compounds. [95b]

MacMillan and co-workers applied Togni’s reagent in an enantioselective α-trifluoromethylation of aldehydes via organocatalytic enamine formation (Scheme  [47] ). [96] The transformation is both high-yielding and highly enantio­selective using catalytic iron(II) or copper(I) salts together with imidazolidinone catalyst 17.

Scheme 47 Enantioselective, organocatalyzed trifluoromethylation

There are few reports on other types of perfluoroalkylations of carbonyl compounds. Umemoto developed (perfluoroalkyl)phenyliodonium triflates as perfluoro­alkyl­-ation reagents of various nucleophiles. The yields obtained in reactions with enolates were, however, moderate due to formation of both O- and C-perfluoroalkylated products. [97]

5 Arylation

α-Arylated carbonyl compounds are commonly occurring subunits in biologically active molecules and are therefore of high interest to the pharmaceutical industry. [98] The introduction of aryl moieties to the α-position of carbonyl compounds, particularly in an asymmetric fashion, is an ongoing challenge in organic synthesis. [98] Conventional procedures often use stoichiometric amounts of toxic reagents and harsh reaction conditions. There are several metal-catalyzed methods to accomplish α-arylation using aryl halides, but these routes suffer from high temperatures, long reaction times and drawbacks associated with the use of heavy metals in industry. [²] [99]

Diaryliodonium salts and other hypervalent iodine reagents provide a means by which α-arylation can be achieved without the need for toxic or expensive transition-metal reagents.

5.1 Arylation with Diaryliodonium Salts

5.1.1. General α-Arylation Strategies

Beringer and co-workers reported the first α-arylation of carbonyl compounds using diaryliodonium salts in 1960. [¹00] Phenylation of a cyclic 1,3-dione with diphenyl­iodonium chloride was achieved in 22% yield, together with 23% of the bis-phenylated product (Scheme  [48] ). The reaction was also conducted using (2-nitrophenyl)phenyliodonium bromide, which resulted in chemoselective transfer of only the 2-nitrophenyl group, that is, the most electron-deficient arene.

Scheme 48 The first reported α-arylation of a diketone using a di­aryliodonium salt

Beringer et al. subsequently investigated the α-arylation of other carbonyl compounds, and reported moderate-yielding arylations of 1,3-indanediones, [¹0¹] malonates, [¹0²] esters and β-keto esters, [¹0³] and 1-indanones. [¹04] tert-Butanol was used as the solvent, and sodium or potassium tert-butoxide as base, throughout these investigations. Similar conditions were later employed in the arylation of Meldrum’s acid. [¹05]

The arylation of diones was further investigated by Hampton­ and co-workers, who performed the phenylation of 2,4-pentanedione using sodamide in liquid ammonia. [¹06] It was possible to conduct this reaction on a multigram scale, furnishing the product in up to 64% yield. [¹07]

In the arylation of ketones, Ryan and Stang used lithium diisopropylamide to generate the lithium enolate of cyclohexanone. [¹08] Treatment of the enolate with diphenyliodonium triflate was found to yield less than 5% of the desired product, improving to 50% on addition of one equivalent of copper(I) cyanide (Scheme  [49] ). A mixture containing a 1:1:2 ratio of product, cyclohexanone and iodobenzene was obtained. It was also noted that five-membered cyclic ketones furnished diarylated products, whereas larger rings were only monoarylated.

Scheme 49 Copper-mediated arylation of cyclohexanone

Using a similar strategy, Gao and Portoghese were able to arylate a highly substituted ketone using diphenyliodonium iodide and lithium hexamethyldisilazide as the base. Under these conditions, the reaction delivered the monophenylated product diastereoselectively in 71% yield, without scrambling the α-stereocenter already present in the starting material (Scheme  [50] ). [¹09] The reaction was used as a key step in the synthesis of a series of 7-arylmorphinans to be tested for opioid agonist and antagonist activity. [¹¹0]

Scheme 50 Diastereoselective phenylation of morphinan-6-ones

In 1999, a highly efficient arylation of malonates was reported by Oh et al. (Scheme  [5¹] ). [¹¹¹] In this extensive study, the preference for transfer of the electron-deficient aryl moiety of an unsymmetrical diaryliodonium salt was reaffirmed. It was also shown that addition of a palladium catalyst does not improve the reaction outcome, and that an aryl iodide cannot be used in place of the diaryliodonium salt.

Scheme 51 Chemoselectivity in aryl group transfer

As an alternative strategy to direct arylation of ketones, silyl enol ethers react with diaryliodonium fluorides to deliver α-arylated ketones. The use of salts with fluoride anions to activate the silyl enol ethers means that no base is needed, thereby avoiding problems with diarylation and scrambling of stereocenters.

In 1991, Chen and Koser demonstrated the arylation of silyl enol ethers using diphenyliodonium fluoride. Either α-phenyl or α,α-diphenyl ketones were produced in 20-88% yield; cyclic substrates were, in general, more suitable than acyclic substrates. [¹¹²]

Rawal and co-workers were able to arylate trimethylsilyl enol ethers using (2-nitrophenyl)phenyliodonium fluoride (Scheme  [5²] ). [¹¹³] As previously reported, only the electron-deficient 2-nitrophenyl group was transferred. This methodology was applied in the total synthesis of tabersonine, an Aspidosperma alkaloid. [¹¹4]

Scheme 52 Chemoselective arylation of trimethylsilyl enol ethers

5.1.2 Asymmetric α-Arylation Strategies

A general asymmetric α-arylation of carbonyl compounds remains elusive. Metal-catalyzed strategies have been presented only for a very limited substrate class, and asymmetric reactions using diaryliodonium salts are conspicuous by their almost complete absence. To date, only two asymmetric α-arylations of this type have been reported.

In 1999, Ochiai et al. utilized chiral diaryliodonium salts based on a binaphthyl core in the arylation of β-keto esters. [¹¹5] Use of the standard tert-butoxide/tert-butanol system enabled the arylation to proceed with up to 53% ee (Scheme  [5³] ). Although the enantiomeric purity of the products was moderate, this paper remains the sole example of an asymmetric α-arylation where the diaryliodonium salt is the source of the asymmetric induction.

Scheme 53 Asymmetric arylation using chiral iodonium salts

The second example employs a chiral base to desymmetrize 4-substituted cyclohexanones prior to arylation. This strategy was successfully used by Aggarwal and Olofsson in a short and elegant total synthesis of (-)-epibatidine (Scheme  [54] ). [¹¹6]

Scheme 54 Asymmetric arylation using Simpkins’ base

Olofsson and co-workers recently reported two attempts towards asymmetric arylation. The first approach involved the use of a diaryliodonium salt bearing a chiral anion. Camphorsulfonate was used as the chiral anion to direct the electrophile to one face of the enolates of cyclic β-keto esters, but the products were racemic under all tested conditions (Scheme  [55] ). [¹¹7]

Scheme 55 Attempted asymmetric arylation with a chiral anion

Next, the same substrates were treated with achiral di­aryliodonium salts under chiral phase-transfer catalysis (PTC*) conditions. The chosen PTC* cation should have blocked one face of the enolates, as demonstrated in asymmetric SNAr reactions of the same substrates. [¹¹8] However, the obtained products were racemic (Scheme  [56] ). [¹¹7]

Scheme 56 Attempted asymmetric arylation with a chiral phase-transfer catalyst

5.1.3 Mechanistic Studies of α-Arylation

In the 1960s, Beringer proposed a radical mechanism for the arylation of carbonyl compounds using diaryliodonium salts [¹0¹] [¹¹9] which was subsequently supported by a number of publications from other research groups. [¹06] [¹¹²] Although this type of mechanism indeed could be operative under certain conditions, later studies have provided evidence for a non-radical mechanism, as detailed below.

Oh et al. proposed that an addition-elimination mechanism operates in the arylation of malonates, as no radical byproducts could be detected (Scheme  [57] ). [¹¹¹]

Scheme 57 Proposed mechanism for the arylation of malonates

In 2003, Ochiai performed a detailed mechanistic study on the α-phenylation of β-keto esters with diaryliodonium salts. The results of intramolecular aryl radical trapping experiments further disputed radical intermediates; instead, a tandem ligand-exchange-ligand-coupling mechanism was proposed (Scheme  [58] ). Polarized transition states were suggested to account for the preferred coupling of enolates with the more electron-deficient phenyl group in unsymmetric salts. [¹²0]

Scheme 58 Ochiai’s mechanistic study

Prompted by the unsuccessful attempts towards asymmetric arylation using chiral anions or chiral phase-transfer catalyst (vide supra), Norrby and Olofsson undertook a mechanistic study using quantum mechanical calculations. The energy difference between neutral Ar2IX and the cationic Ar2I+ were too small to allow a distinct starting point in the reaction with the enolate (Scheme  [59] ). Two intermediates, with oxygen or carbon bonded to iodine, were identified as isoenergetic. These form the product through different reductive elimination mechanisms: [2,3] rearrangement or [1,2] rearrangement, respectively, where the first pathway is favored. [¹¹7]

The most important finding was that the isomerization barrier between the C-I and O-I intermediate was low enough (16 kJ˙mol-1) to give a fast equilibration. Thus, any asymmetric induction obtained in the formation of a C-I intermediate will be lost by equilibration with the O-I intermediate. This is in good agreement with the lack of selectivity observed in the experimental work (vide supra). [¹¹7]

Scheme 59 Proposed mechanism based on calculations

5.2 Arylation with Other Reagents

Kita et al. have thoroughly investigated the reactions of phenol ethers with PIFA and various nucleophiles. When para-substituted phenol ethers were used in polar, poorly nucleophilic protic solvents such as 2,2,2-trifluoroethanol (TFE) or 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP), nucleophilic substitution ortho to the ether substituent took place in moderate yields. In this fashion, β-diketones and β-keto esters could be employed as nucleophiles to deliver α-arylated products (Scheme  [60] ). [¹²¹]

Scheme 60 Kita’s arylation with PIFA

The mechanism is believed to involve formation of cationic radicals via single-electron transfer (SET) from an initially formed charge-transfer complex, followed by nucleophilic attack (Scheme  [6¹] ). [¹²¹]

Scheme 61 Mechanism for arylation with PIFA

This transformation was subsequently employed in the synthesis of benzannulated and spirobenzannulated compounds. The use of phenol ethers bearing a cyclic 1,3-dicarbonyl moiety as the para substituent resulted in intramolecular cyclization onto the meta position (Scheme  [6²] ). [¹²²]

Phenol ethers with meta substituents could also be employed in this transformation; cyclization occurred re­gioselectively in the para position because of steric hindrance. Substrates containing acyclic dicarbonyls gave no arylation in either case. [¹²²]

Scheme 62 Intramolecular α-arylation with PIFA

Another intramolecular α-arylation was achieved by a Pummerer-type reaction of α-acyl sulfides with PIFA, forming various heterocyclic structures (Scheme  [6³] ). [¹²³]

Scheme 63 PIFA-mediated Pummerer-type reaction

A sequential aminopalladation/C-H activation reaction of alkynyl amides 18 was recently reported. When treated with palladium(II) acetate and PIDA, the alkyne was difunctionalized to produce α-arylated amides 19 in good yields (Scheme  [64] ). [¹²4]

Scheme 64 Aminopalladation/C-H activation reaction

6 Alkynylation and Alkenylation

Reactions of certain enolates with alkynyl(aryl)iodonium salts [8] [¹²5] and alkenyl(aryl)iodonium salts [¹²6] led to α-alkynylated and α-alkenylated products, respectively. Reports on these transformations are scarce when compared to those on α-arylations (vide supra), and the chemoselectivity versus α-arylation can pose a problem. The reactions of these iodonium salts proceed via mechanisms other than those with diaryliodonium salts, and different reaction pathways are followed, depending on the structure of the salt, the nucleophile and the reaction conditions employed. [8] [¹²5] [¹²6]

Beringer demonstrated the α-alkynylation and α-alkenylation of 2-phenylindane-1,3-dione using iodonium salts (Scheme  [65] ). [¹²7] The reactions were performed under the same conditions as the research group’s reported α-arylations (see section 5.1.1), namely, using sodium tert-butoxide in refluxing tert-butanol.

Scheme 65 Alkynylation and alkenylation with iodonium salts

In 1986, Ochiai reported an efficient cyclopentene annulation using alkynyliodonium salts (Scheme  [66] ). [¹²8] The reaction proceeds via a tandem Michael-carbene insertion to form the annulated product in good yield.

Scheme 66 Cyclopentene annulation

Kitamura et al. later continued this theme using alkynyliodonium salts containing an o-carboxyphenyl moiety to facilitate recovery of the iodoarene. [¹²9] Upon reaction with 2-phenylindane-1,3-dione, alkynylation or alkenylation was obtained, depending on the alkynyl substituent in the iodonium salt.

α-Ethynylation of a range of 1,3-dicarbonyl compounds can be achieved in good yields using ethynyl(phenyl)iodonium tetrafluoroborate. [¹³0]

Bachi and Stang investigated the alkynylation of an iminomalonate using variously substituted alkynyliodonium salts (Scheme  [67] ). The products were obtained in moderate to good yield, and are useful precursors to α-alkynyl-α-amino carboxylic acid derivatives. [¹³¹] The same research group also reported the reaction of 2-oxoazetidin-1-yl­malonates with trimethylsilyl-protected alkynyliodonium salts, delivering products with a terminal alkynyl group. [¹³²]

Scheme 67 Alkynylation of an iminomalonate

Ochiai reported a chemoselective α-alkenylation of 1,3-dicarbonyl compounds with alkenyl(aryl)iodonium tetrafluoroborates (Scheme  [68] ). [¹³³] Competing α-arylation could be avoided by using a p-methoxyphenyl moiety. In this detailed study, the use of an aryl radical trap inhibited radical-induced decomposition of the alkenyl(aryl)iodonium salts, thereby improving the yields. The reaction works for cyclic β-keto esters, 1,3-diketones and 1,3-diesters.

Scheme 68 Alkenylation using a radical trap

In 2010, Waser and co-workers developed a very reactive ethynylation reagent (20), formed in situ from benziodoxolone 21 [Scheme  [69] (a)]. [¹³4] This reagent ethynylated cyclic and acyclic β-keto esters, 1,3-diesters, as well as cyano and nitro esters, in high yields. One enantioselective example was presented, in which a chiral phase-transfer catalyst was employed to give moderate asymmetric induction [Scheme  [69] (b)]. [¹³4]

Scheme 69 Ethynylation of 1,3-dicarbonyl compounds

7 Homocoupling

The oxidative coupling of two carbonyl compounds to form 1,4-dicarbonyl compounds is of interest as the target compounds are versatile intermediates in the synthesis of natural products. This transformation can be performed using a range of oxidants, including hypervalent iodine reagents. [¹³5]

Early investigations by Moriarty et al. showed that aryl methyl ketones, when converted into the corresponding trimethylsilyl enol ethers, could be homocoupled using iodosobenzene and boron trifluoride-diethyl ether complex. The butane-1,4-dione products were formed in moderate yields. [56] [¹³6]

The research groups of Caple and Zefirov later developed iodosobenzene tetrafluoroborate and iodosobenzene hexafluorophosphate as stable and superior reagents for the homocoupling of trimethylsilyl enol ethers (Scheme  [70] ). [¹³7] These reagents were also efficient in the coupling of aliphatic substrates.

Scheme 70 Oxidative homocoupling of silyl enol ethers

The same research groups reported the use of PhIO˙HBF4; with this reagent a stepwise approach enabling heterocouplings between two different trimethylsilyl enol ethers was possible. [¹³8]

Direct homocoupling of carbonyl compounds, rather than the corresponding silyl enol ether, was reported by Moriarty­ in 1988. [70] β-Diketones and β-keto esters were treated with iodosobenzene and boron trifluoride-diethyl ether complex to give homocoupled products (Scheme  [7¹] ).

Scheme 71 Homocoupling of 1,3-dicarbonyl compounds

Chen and co-workers employed substituted derivatives of Meldrum’s acid with PIDA, potassium carbonate and a phase-transfer catalyst to give homocoupled products in moderate yield (Scheme  [7²] ). [¹³9]

Scheme 72 Homocoupling of Meldrum’s acid

More recently, the homocoupling of enolates derived from oxazolidinones and imidazolidinones has been reported. [¹40] When chiral substrates were employed, moderate to good diastereoselectivities were observed in the coupling (Scheme  [7³] ). [¹40b] A radical mechanism was postulated.

Scheme 73 Homocoupling of chiral substrates

8 Functionalization of α,β-Unsaturated Carbonyl Compounds

Hypervalent iodine compounds are generally used as electrophilic reagents in reactions with nucleophiles. Oxidation of the alkene moiety in α,β-unsaturated carbonyl compounds requires a nucleophilic reagent, and most of the reactions presented below utilize another reagent for this purpose, followed by oxidation of the resulting intermediate with the hypervalent iodine reagent. In certain cases, however, the hypervalent iodine compound is used without aid from other reagents. [¹4¹]

8.1 Epoxidation

In 2000, Ochiai et al. developed the first hypervalent iodine compound that could epoxidize enones (Scheme  [74] ). The reagent, tetrabutylammonium oxido-λ³-iodane, contains an oxyanion that can attack the electron-deficient olefin; this is followed by a ring closure to form the epoxide and expel the iodoarene. [¹4²]

Scheme 74 Epoxidation of enones

The epoxidation of a range of cyclic, highly electron-deficient enones was demonstrated using iodosylbenzene. [¹4³] While limited in scope, this method gave high yields under mild reaction conditions.

A chemo- and stereoselective epoxidation of an advanced intermediate in the synthesis of epoxysorbicillinol was realized in excellent yield using PIFA (Scheme  [75] ). [¹44]

Scheme 75 Epoxidation with PIFA

A one-pot conversion of enones into the corresponding α,β-epoxy ketones was recently developed using sequential addition of IBX-I2 and 10% sodium hydroxide. The reaction proceeds via iodohydroxylation (see section 8.4) followed by base-induced ring closure (Scheme  [76] ). [¹45]

Scheme 76 Epoxidation with IBX

Lee and MacMillan reported an enantioselective, organocatalytic epoxidation of α,β-unsaturated aldehydes. [¹46] An imidazolidinone catalyst was employed to form an enamine intermediate with the aldehyde (cf. section 4), which was subsequently epoxidized by iodosobenzene. To circumvent unwanted oxidation of the catalyst, an ‘internal syringe pump’ strategy was devised using [(nosylimino)iodo]benzene, which slowly released PhIO under the reaction conditions. The protocol was applied to a range of α,β-unsaturated aldehydes, giving the corresponding epoxides in good yields and high enantiomeric excess (Scheme  [77] ). [¹46]

Scheme 77 MacMillan’s enantioselective epoxidation

8.2 Aziridination

In 1991, Evans et al. reported the first aziridination of α,β-unsaturated carbonyl compounds with a hypervalent iodine reagent. [¹47] The reaction was catalyzed with copper salts and used [N-(p-tolylsulfonyl)imino]phenyliodinane (PhI=NTs) as the nitrene precursor, providing N-tosyl­aziridines in moderate yields. An improved procedure was later presented in which α,β-unsaturated esters were aziridinated in good yields (Scheme  [78] ). [¹48] Unsaturated ketones were less reactive, and provided only trace amounts of product.

Scheme 78 Aziridination of α,β-unsaturated esters

An enantioselective version of this reaction was developed wherein bis(oxazoline)-copper complexes were employed as catalysts to give aziridinated products in good yields and high enantiomeric excess (Scheme  [79] ). [¹49]

Scheme 79 Evans’ enantioselective aziridination

Jacobsen and co-workers reported a similar catalytic system, employing bifunctional Schiff bases derived from trans-1,2-diaminocyclohexane. [¹50] Other groups have also developed ligands useful for asymmetric aziridination of α,β-unsaturated esters under similar conditions. [¹5¹]

A one-pot enantioselective aziridination of α,β-unsaturated esters was accomplished by using a sulfonamide and PIDA combination as the nitrene source with copper catalysis, although the yields were not comparable with those of reactions using PhI=NTs. [¹5²]

Yudin and co-workers developed a metal-free aziridination of chalcones by combination of PIDA and N-aminophthalimide, resulting in good yields of aziridines under mild conditions (Scheme  [80] ). [¹5³]

Scheme 80 PIDA-mediated aziridination; Phth = phthalimide

An asymmetric aziridination of chalcones was developed by Xu et al. in 2004. [¹54] The use of more rigid bis(oxazoline)-copper complexes in dichloromethane delivered aziridines in moderate to good yields and high enantioselectivity (Scheme  [8¹] ). [¹55]

Scheme 81 Asymmetric aziridination of chalcones

8.3 Aminohalogenation

Wang and co-workers have reported several aminohalogenations of enones using PIDA. Aminochlorination was performed under solvent-free conditions using chloramine-T and PIDA, giving α-amino-β-chloro ketones with high diastereoselectivities and complete regioselectivities. Chalcones were the best substrates, but esters and amides also underwent this transformation (Scheme  [8²] ). [¹56] The reaction could also be conducted without PIDA under phase-transfer conditions. [¹57]

Scheme 82 Aminochlorination of enones

Likewise, aminobromination of enones was achieved under solvent-free conditions using tosylamine, N-bromosuccinimide and a catalytic amount of PIDA. Also in this case, high stereoselectivities and good yields were observed. [¹58] The reaction could also be performed in water at elevated temperature. [¹59]

8.4 Other Functionalizations

In 1984, Rebrovic and Koser reported a vicinal ditosyloxylation of alkenes using HTIB. One example of ditosyloxylation of an enone was presented; chalcone delivered the disubstituted product in 57% yield. [¹60] This methodology was recently applied to several aromatic enones in good yield (Scheme  [8³] ). [¹6¹]

Scheme 83 Ditosyloxylation of chalcones

Iodohydroxylation of α,β-unsaturated carbonyl compounds can be performed using the IBX-I2 redox couple in dimethylsulfoxide. Enones, α,β-unsaturated esters and amides are tolerated in this reaction. The active reagent is hypoiodous acid (IOH), which adds to the olefin with high anti stereoselectivity (Scheme  [84] ). [¹45] A one-pot conversion into the corresponding epoxide was also developed (see section 8.1).

Scheme 84 Iodohydroxylation mediated by IBX

Chalcones can undergo oxidative rearrangement in the presence of HTIB. [¹6²] The reaction can also be performed using PIFA, [¹6³] or PIDA in the presence of p-toluenesulfonic acid (Scheme  [85] ). [¹64] This transformation has been employed as a key step in the synthesis of isoflavone natural products. [¹65] Under certain conditions, the aryl moiety attached to the carbonyl group (Ar¹) migrates instead. [¹66]

Scheme 85 Oxidative rearrangement of chalcones

α,β-Unsaturated aldehydes and ketones can be chlorinated or brominated in the α-position in good yields using PIDA and the hydrochloride or hydrobromide salt of pyridine. [¹67] Uracil bases and protected nucleosides can be chlorinated in excellent yield using (dichloroiodo)benzene. [¹68] Dihydropyridones can be iodinated using N-iodosuccinimide and a catalytic amount of HTIB (Scheme  [86] ). [¹69]

Scheme 86 Iodination of dihydropyridones

Oxidative spirocyclization of phenols is an important PIFA-mediated transformation. [¹²] Using this methodology, intramolecular oxidation of O-silylated phenols bearing various types of aminoquinones at the para position gave azacarbocyclic spiro dienones in good yields (Scheme  [87] ). [¹70] This reaction was applied in the total synthesis of discorhabdin C.

Scheme 87 Synthesis of azacarbocyclic spiro dienones

A certain type of iodonium ylide, called iodonium bis(sulfonyl)methylide, was shown to react with enones in a [3+2] cycloaddition catalyzed by rhodium(II) acetate, delivering arylindanes in moderate yields (Scheme  [88] ). [¹7¹]

Scheme 88 Cycloaddition of enones with iodonium ylides

9 Miscellaneous

Moriarty reported the α-azidation of 1,3-dicarbonyl compounds in 1988. [70] β-Diketones and β-keto esters were treated with iodosobenzene and trimethylsilylazide to give azido-substituted products (Scheme  [89] ).

Scheme 89 Azidation of 1,3-dicarbonyl compounds

The α-azidation of ketones can be performed by sequential treatment with [hydroxy(p-nitrobenzenesulfonyl­oxy)iodo]benzene (HNIB), forming an α-sulfonyloxy intermediate (see sections 2.1 and 3.3), and then with sodium azide (Scheme  [90] ). [¹7²] Replacement of HNIB with HTIB resulted in reduced yields. This transformation is analogous to the iodination shown in Scheme  [4³] .

Scheme 90 Azidation of ketones

A similar approach using sequential addition of HTIB and sodium sulfinate to ketones delivered the corresponding β-keto sulfones in moderate to good yields. [¹7³]

Prakash and Moriarty reported that the combination of (dichloroiodo)benzene and lead(II) thiocyanate effects thiocyanation of β-keto esters and 1,3-diketones (Scheme  [9¹] ). [¹74] [Bis(thiocyanato)iodo]benzene is believed to be the active reagent in this process. Ketones and esters are not reactive under these conditions, but the α-thiocyanated products can be obtained from the corresponding silyl enol ethers. [¹74] An improved method for thiocyanation of 2-arylindane-1,3-diones was later found, where (dichloroiodo)benzene was combined with potassium thiocyanate. [¹75]

Scheme 91 Thiocyanation of dicarbonyl compounds

A PIDA-mediated oxidative addition of cyclic and acyclic 1,3-dicarbonyl compounds to olefins provides an efficient synthesis of 2,3-dihydrofuran derivatives (Scheme  [9²] ). [¹4¹]

Scheme 92 Synthesis of 2,3-dihydrofuran derivatives

Metal-catalyzed aziridination of silyl enol ethers and silyl ketene acetals with PhI=NTs provides α-tosylamido carbonyl compounds. [¹48] The details of this transformation, however, fall outside the scope of this review.

Very recently, Ishihara and co-workers presented an enantioselective oxidative cycloetherification. The reaction was stoichiometric in hydrogen peroxide, and employed chiral quaternary ammonium iodide catalyst 22 as the source of asymmetric induction (Scheme  [9³] ). [¹0c] A wide range of cyclized products were obtained in excellent yields and enantioselectivities. The active oxidant was proposed to be hypoiodite (IO-) or iodite (IO2 -), formed by hydrogen peroxide oxidation of the iodide.

Scheme 93 Ishihara’s enantioselective cycloetherification

10 Summary

This review has summarized the use of hypervalent iodine reagents in the α-functionalization of carbonyl compounds, delivering a diverse set of products under mild reaction conditions. With the development of catalytic and asymmetric hypervalent iodine mediated α-functionalization reactions over the past decade, these compounds show great potential as environmentally benign and selective reagents for many yet-undiscovered transformations.

Acknowledgment

Our research in the area of hypervalent iodine chemistry has been supported by the Swedish Research Council, Wenner-Gren Foundations, Carl Trygger Foundation, the Royal Swedish Academy of Sciences and K & A Wallenberg Foundation.

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Figure 1 Commonly used hypervalent iodine reagents

Scheme 1 Koser’s α-tosyloxylation of ketones using HTIB

Scheme 2 α-(10-Camphorsulfonyl)oxylation of carbonyls

Scheme 3 Novel [hydroxy(tosyloxy)iodo]arenes used by Nabana and Togo

Scheme 4 2,4-Dinitrobenzenesulfonic acid in α-oxygenation of ketones; DNs = 2,4-dinitrobenzenesulfonyl

Scheme 5 Synthesis of symmetrical keto disulfides from enolizable ketones

Scheme 6 4-Iodotoluene-mediated α-tosyloxylation of ketones

Scheme 7 α-Oxygenation using TolIF2

Scheme 8 Use of iodosylbenzene in α-tosyloxylation reactions

Scheme 9 Wirth’s use of iodoxolone-based reagents

Scheme 10 Karade’s DMP-derived α-tosyloxylation reagent

Scheme 11 Iodine(V) in α-sulfonyloxylation reactions

Scheme 12 Polymer-bound HTIBs: PS = polystyrene, average molecular weight 45,000; PMS = poly(α-methylstyrene), average molecular weight 6,200

Scheme 13 Polystyrenesulfonic acid resin-based HTIB derivative

Figure 2 Recyclable HTIB reagents used in α-tosyloxylation reactions

Scheme 14 Ionic liquid supported Koser’s reagent

Scheme 15 Iodobenzene-catalyzed α-tosyloxylation

Scheme 16 Asymmetric α-tosyloxylation of propiophenone

Scheme 17 Catalytic asymmetric α-sulfonyloxylation of ketones

Figure 3 Enantiomerically pure esters used in the asymmetric α-tosyloxylation of propiophenone

Scheme 18 α-Hydroxylation of ketones using iodosylbenzene

Scheme 19 Preparation of α-hydroxycarboxylic acids or α-alkoxy esters from esters using PIDA

Scheme 20 α-Hydroxylation of ketones under acidic conditions

Scheme 21 Polymer-supported PIDA in the synthesis of α-hydroxy ketones

Scheme 22 Examples of IBX-mediated α-hydroxylation reactions

Scheme 23 Iodobenzene-catalyzed α-hydroxylation of ketones

Scheme 24 Organocatalytic asymmetric α-hydroxylation of ke­tones

Scheme 25 Acetoxylation of acetophenones using PIDA

Scheme 26 Ochiai’s iodobenzene-catalyzed α-acetoxylation of ketones

Scheme 27 α-Acyloxylation of ketones

Scheme 28 α-Phosphorylation of ketones

Scheme 29 Synthesis of α-(2-iodobenzoyloxy)ketones

Scheme 30 Synthesis of aroylcoumaranones

Scheme 31 Synthesis of arylfuranones

Scheme 32 Synthesis of furanones via iodonium ylides

Scheme 33 Preparation of lactones from 5-keto acids

Scheme 34 Iodobenzene-catalyzed lactonization reaction

Scheme 35 Synthesis of fused dihydrofurans (a) and proposed mechanism for the [1,5]-oxidative cyclization of Michael adducts (b)

Scheme 36 Monofluorination under neutral conditions

Scheme 37 Fluoro-Pummerer reaction

Scheme 38 Chlorination of phosphonium ylides

Scheme 39 Asymmetric α-chlorination (1-Nph = naphthalen-1-yl)

Scheme 40 Chlorination of dicarbonyl compounds with PIDA

Scheme 41 Umpolung strategy for chlorination

Scheme 42 Bromination of dicarbonyl compounds with PIDA

Scheme 43 Sequential iodination of ketones

Scheme 44 Sequential halogenation of ketones

Figure 4 Togni’s trifluoromethylation reagents

Scheme 45 Trifluoromethylation of β-keto esters (NMR yields)

Scheme 46 Trifluoromethylation and reduction to α-amino acid (NMR yields)

Scheme 47 Enantioselective, organocatalyzed trifluoromethylation

Scheme 48 The first reported α-arylation of a diketone using a di­aryliodonium salt

Scheme 49 Copper-mediated arylation of cyclohexanone

Scheme 50 Diastereoselective phenylation of morphinan-6-ones

Scheme 51 Chemoselectivity in aryl group transfer

Scheme 52 Chemoselective arylation of trimethylsilyl enol ethers

Scheme 53 Asymmetric arylation using chiral iodonium salts

Scheme 54 Asymmetric arylation using Simpkins’ base

Scheme 55 Attempted asymmetric arylation with a chiral anion

Scheme 56 Attempted asymmetric arylation with a chiral phase-transfer catalyst

Scheme 57 Proposed mechanism for the arylation of malonates

Scheme 58 Ochiai’s mechanistic study

Scheme 59 Proposed mechanism based on calculations

Scheme 60 Kita’s arylation with PIFA

Scheme 61 Mechanism for arylation with PIFA

Scheme 62 Intramolecular α-arylation with PIFA

Scheme 63 PIFA-mediated Pummerer-type reaction

Scheme 64 Aminopalladation/C-H activation reaction

Scheme 65 Alkynylation and alkenylation with iodonium salts

Scheme 66 Cyclopentene annulation

Scheme 67 Alkynylation of an iminomalonate

Scheme 68 Alkenylation using a radical trap

Scheme 69 Ethynylation of 1,3-dicarbonyl compounds

Scheme 70 Oxidative homocoupling of silyl enol ethers

Scheme 71 Homocoupling of 1,3-dicarbonyl compounds

Scheme 72 Homocoupling of Meldrum’s acid

Scheme 73 Homocoupling of chiral substrates

Scheme 74 Epoxidation of enones

Scheme 75 Epoxidation with PIFA

Scheme 76 Epoxidation with IBX

Scheme 77 MacMillan’s enantioselective epoxidation

Scheme 78 Aziridination of α,β-unsaturated esters

Scheme 79 Evans’ enantioselective aziridination

Scheme 80 PIDA-mediated aziridination; Phth = phthalimide

Scheme 81 Asymmetric aziridination of chalcones

Scheme 82 Aminochlorination of enones

Scheme 83 Ditosyloxylation of chalcones

Scheme 84 Iodohydroxylation mediated by IBX

Scheme 85 Oxidative rearrangement of chalcones

Scheme 86 Iodination of dihydropyridones

Scheme 87 Synthesis of azacarbocyclic spiro dienones

Scheme 88 Cycloaddition of enones with iodonium ylides

Scheme 89 Azidation of 1,3-dicarbonyl compounds

Scheme 90 Azidation of ketones

Scheme 91 Thiocyanation of dicarbonyl compounds

Scheme 92 Synthesis of 2,3-dihydrofuran derivatives

Scheme 93 Ishihara’s enantioselective cycloetherification