Organoindium Reagents: The Preparation and Application in Organic

Review pubs.acs.org/CR

Organoindium Reagents: The Preparation and Application in Organic Synthesis Zhi-Liang Shen,‡ Shun-Yi Wang,‡ Yew-Keong Chok,‡ Yun-He Xu,†,‡ and Teck-Peng Loh*,†,‡ †

Department of Chemistry, University of Science and Technology of China, Hefei 230026, P. R. China Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371

‡

6. 7. 8. 9.

Benzylindium Reagent Arylindium Reagent Alkylindium Reagent Alkynylindium Reagent 9.1. Introduction and Preparative Method 9.2. Application in Organic Synthesis 10. Alkenylindium Reagent from Carboindation 10.1. Introduction and Preparative Method 10.2. Application in Organic Synthesis 11. Triorganoindium Reagent 11.1. Introduction 11.2. Preparative Method 11.3. Application in Organic Synthesis 12. Organoindate (Tetraorganoindium) Reagent 12.1. Introduction and Preparative Method 12.2. Application in Organic Synthesis 13. (Organothio)indium and (Organoseleno)indium Reagent 13.1. Introduction 13.2. Preparative Method 13.3. Application in Organic Synthesis 14. Miscellaneous Organoindium Reagents 14.1. Cyclopentadienylindium(I) 14.2. Intramolecularly Stabilized Dialkyl Indium Complexes 15. Conclusion and Future Outlook Author Information Corresponding Author Notes Biographies Acknowledgments References

CONTENTS 1. Introduction 2. Allylindium Reagents 2.1. Introduction 2.2. Preparative Method 2.3. Nature of Allylindium Reagent 2.4. Addition to Carbonyl Compound 2.4.1. Different Solvent Media 2.4.2. Versatility of Carbonyl Compound and Related Derivative 2.4.3. Versatility of Allyl Substrate 2.4.4. Catalytic Amount of Indium and Recovery of Indium 2.4.5. α,γ-Selectivity of Allylindium Reagent 2.4.6. Diastereoselectivity 2.4.7. Enantioselectivity 2.4.8. Application in Natural and Unnatural Product Synthesis 2.4.9. Intramolecular Addition 2.5. Addition to Imine 2.5.1. Addition to Imine and Related Derivative 2.5.2. Diastereoselectivity 2.5.3. Enantioselectivity 2.6. Addition to Alkene and Alkyne 2.7. Addition to Nitrile and Its Derivative 2.8. Cross-Coupling Reaction 2.9. Addition to Miscellaneous Electrophiles 3. Propargylindium and Allenylindium Reagent 3.1. Introduction and Preparative Method 3.2. Application in Organic Synthesis 4. Indium Enolate 4.1. Introduction and Preparative Method 4.2. Application in Organic Synthesis 5. Indium Homoenolate © 2012 American Chemical Society

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1. INTRODUCTION During the last century, organometallic reagents prepared from main group metals,1 such as organolithium, organomagnesium, and organozinc compounds, have played a central role in the advancement of synthetic organic chemistry. However, the sensitivity of these reactive organometallic species to moisture and air rendered the preparation and handling of these reagents difficult. In addition, the poor compatibility of these organometallic compounds toward important functionalities such as carbonyl and hydroxyl groups also limited their widespread application in organic synthesis. In these regards, organoindium

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Received: February 9, 2012 Published: October 31, 2012 271

dx.doi.org/10.1021/cr300051y | Chem. Rev. 2013, 113, 271−401

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Functional groups such as hydroxyl group can be used directly without resorting to often onerous protection and deprotection manipulations. (2) Water-soluble carbohydrate substrates can be directly functionalized by organoindium reagents in water. (3) The preparation and handling of organoindium reagent is simplified because, in most cases, no exclusion of moisture and predrying of the reagent and glassware are required. (4) In addition, operation of organoindium reagents in water is possible and attractive from both economic and environmental standpoints, especially in the context of modern Green Chemistry. (5) Finally, the mildness of organoindium reagent usually minimizes the occurrence of side-reactions such as βhydride elimination and Wurtz-type homocoupling, which are frequently encountered in the use of other more reactive organometallic compounds. Another distinctive advantage of using organoindium compounds is that both indium metal and its derivatives are less toxic or even nontoxic.58 In addition, the byproduct generated after the reaction of organoindium compounds, normally indium(III) halides, are also nontoxic. On the contrary, most organotin and organolead compounds are toxic and thus suffer from limited applications in organic synthesis. These intriguing features of organoindium compounds also render better selectivities in organic transformations that are difficult to achieve by using other organometallic reagents. Organic chemists have noticed in many cases that organoindium reagents exhibited better performance than their organomagnesium and organozinc counterparts. Thus, the unique property of organoindium reagent also confers specific reactivity for carbon−carbon bond formations, allowing organic transformations to proceed with better selectivities (e.g., product yield and chemoselectivity).39,59−115 In past decades, a variety of articles concerning the use of indium compound as reducing agent,116 radical initiator,117 and Lewis acid catalyst118−127 have been reviewed. In addition, the use of indium(0) metal in allylation, propargylation, and analogous reactions have also been, partially or selectively, described.128−144 Three reviews associated with the topic of low-valent indium have been reported as well.145−147 The intent of this review is to provide an overview of the preparation and application of organoindium reagents in organic synthesis. However, to have a complete overview of the developments in organoindium reagents, it is inevitable for this review to have some overlap with the contents in previous review articles or chapters of books, especially with two excellent reviews148,149 recently published in this area. This review covers the literature up to the middle of 2012.

reagent, backed by several decades of development, has emerged as an attractive alternative to the aforementioned reactive organometallic species. To the best of our knowledge, the first preparation of organoindium compound can be traced back to 1934 when Dennis and co-workers2 synthesized trimethylindium (Me3In) via the transmetalation of dimethylmercury with indium.3−6 Prior to 1980, sporadic studies carried out by several groups showed that organoindium reagents also can be accessed from the transmetalation of indium(III) halides with organoaluminum,7 organomagnesium,8−10 and organolithium reagents.11 In addition, the insertion of indium(I) halide or indium(II) dihalide into organohalides also served as alternative methods for the synthesis of various organoindium compounds.12−17 However, most of these earlier works only dealt with the preparation of organoindium reagents (R3In, R2InX, RInX2, etc.) and the studies of their structures and properties, as well as their transformations to other organoindium derivatives.18−34 Very few focused on their applications in organic synthesis, for example, their reactions with electrophiles such as carbonyl compounds.3,35 It was not until 1974 that the first application of indium in organic synthesis was reported by Rieke and co-workers in the Reformatsky reaction of ethyl bromoacetate with carbonyl compound. In this case, a preactivated Rieke indium, which can be prepared from the reduction of indium(III) trichloride by potassium, was used as reaction mediator.36,37 In 1988, a landmark finding disclosed by Araki, Ito, and Butsugan38 showed that commercially available powdered indium readily inserts into allyl halide to generate an allylindium reagent in dimethylformamide (DMF) or tetrahydrofuran (THF), which can react with carbonyl compounds to afford homoallylic alcohols in high efficiency. This work pioneered the potential utility of commercial indium in organic synthesis. Since then, the use of indium and organoindium reagents in organic synthesis had increased steadily. In 1991, another seminal contribution made by Li and Chan,39 who demonstrated the feasibility of carrying out indium-mediated allylation in water, further established the versatility of organoindium reagents in water-based organic reactions, in the context of sustainable Green Chemistry. Later the simple methods for the preparation of arylindium and alkylindium reagents developed by Knochel,40,41 Loh,42 and others further contributed to the use of organoindium reagents in organic synthesis and had increasingly attracted attention from the synthetic community. Starting from 1999, Sarandeses,43,44 Lee,45 and others introduced organoindium reagents in transition metal-catalyzed cross-coupling with various electrophiles, leading to many synthetcically useful organic molecules. Furthermore, a recent advancement made by Baba and others implies that the organoindium reagent prepared by the insertion of indium(0) into organic halides (RX) most possibly exists as a mixture of RInX2 and R2InX,46−49 or their aggregate form of R3In2X3.17 Several representative X-ray crystal structures of organoindium reagents, generated from organic transformations, have also been reported.46−48,50−57 In comparison with the aforementioned reactive organometallic species, one salient feature of an organoindium compound is that most organoindium reagents are mild and relatively stable. They exhibit excellent tolerance toward functional groups such as halide, nitro, nitrile, ester, ketone, active methylene, and even hydroxyl group and water. This unique property is appealing from several aspects: (1)

2. ALLYLINDIUM REAGENTS 2.1. Introduction

As mentioned above, allylindium reagent was first introduced in 1988 by Araki, Ito, and Butsugan for the allylation of carbonyl compounds in DMF.38,150 Three years later, the importance of allylindium reagent was further demonstrated by Li and Chan when they observed that the indium-mediated allylation reaction also can be performed in water, in most cases showing even better performance than the same reaction carried out in organic solvents.39 Other groups such as Loh,151 Paquette,152 and others have contributed by studying the various aspects of simple diastereo-, diastereofacial-, and enantioselectivity of the reaction involving allylindium with aldehydes/imines and 272


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developing new reaction conditions for unreactive substrates, which further expanded the scope and synthetic usefulness of this reagent in organic synthesis. After more than 2 decades of development, organic transformation using allylindium species has proven itself to be a versatile and powerful platform for the synthesis of various useful synthetic intermediates bearing allyl substituents, as well as the key strategy in the synthesis of many natural and unnatural products.

Scheme 3

mesh indium powder, the resulting homoallylic alcohols were afforded with slightly increased syn/anti diastereoselectivities. A recent development made by Li and co-workers showed that a novel indium−boron amorphous alloy (prepared by the reaction of KBH4 with InCl3 and determined to be In83B17) exhibited better reactivity than commercial indium powder, allowing highly efficient allylation of carbonyl compounds in water, even with the use of less reactive allyl chloride.170 Unlike lithium, magnesium, and zinc, indium metal is not sensitive to air and is not known to form an oxide layer on the metal surface. Thus, in most cases, indium can be directly used in an allylation reaction without the need for special activation. In comparison, preactivation is usually required in the use of magnesium and zinc in order to remove the oxide layer formed on their surface. But, in some special cases, it was found that the utilization of ultrasonication,65,171−176 or the addition of protic acid (e.g., HOAc/CF 3 COOH, 1 7 7 − 1 8 5 HCOOH, 1 8 6 HCl,62,86,187−191 etc.), Lewis acid (e.g., La(OTf)3,171,192−197 Yb(OTf)3,198 HfCl4,199−201 InCl3,200−204 and In(OTf)3205), and Bu4NBr190,206 as reaction additives, or the use of aqueous NH4Cl as reaction medium,63,171,180,200−202,207−209 also can lead to enhanced performance of indium-mediated allylation reactions, especially for less reactive allyl substrates. It should be noted that, due to the conversion of indium(0) metal to a byproduct of indium(III) salt during the course of the allylation, the reaction mixture becomes increasingly acidic. This gradual increase in acidity of the reaction medium may also lead to accelerated progress of the reaction, as already observed in several cases.206 In addition, indium does not react with water at ambient temperature, enabling the use of indium in aqueous medium or moisture-laden atmosphere. This valuable aspect simplifies the use of indium in organic reactions because no exclusion of water and predrying of the reagent are required, especially when we compare to the tedious manipulations involved in the preparation of organometallic reagents from magnesium and zinc under strictly anhydrous conditions. The insertion of indium(I) halide into allyl halide can also be used to generate allylindium reagent (Scheme 4).16,210 As

2.2. Preparative Method

The direct insertion of indium(0) into allyl halide serves as an important method for the preparation of allylindium reagent. Both organic and aqueous solvents can be used as reaction media, and allylindium sesquihalide38 (Scheme 1) and Scheme 1

Scheme 2

allylindium(I)153 (Scheme 2) are generally considered to be the allylindium species formed in these two different solvent media, respectively. Usually, allyl iodide and bromide are employed as the substrates. In contrast, allyl chloride is relatively unreactive toward indium insertion under the same conditions, although the use of allyl chloride would be advantageous from an economic point of view. Consequently, we can find in many cases that alkali metal iodide38,60,71,154−167 is added as an additive to in situ convert the less reactive allyl chloride to the corresponding more reactive allyl iodide, which would facilitate ensuing indium insertion. It should be noted that usually the allylindium reagent is prepared in situ with high conversion by mixing indium with the allyl halide, which, once formed, immediately reacts with the added electrophile. Thus, the exact conversion yield of the allyl halide to allylindium reagent has rarely been determined. Indium is often used in the form of a powder as purchased from chemical companies. It was reported that cheaper indium metal in a granular form can be used as well in the allylation of carbonyl compounds.168 By vigorous stirring of the reaction mixture at an elevated temperature of 40−50 °C in DMF, good to excellent yields of the products can be achieved as well. The size of the indium metal also considerably affects the outcome of the allylation reaction. Rieke36,37 indium (average 4.0 μm) prepared from the reduction of indium(III) compound by alkali metal was found to exhibit higher reactivity than the nonactivated one. Also, Wang and co-workers169 discovered that indium nanoparticles (∼100 nm) exhibited greatly improved efficiency in promoting the allylations between carbonyl compounds and less reactive allyl chloride in water (75−99% yields, Scheme 3). In contrast, the same reactions using powdered indium (200 mesh) showed reduced reactivity (38−75% yields). Moreover, when crotyl chloride was used as the substrate in the presence of nanosize indium instead of 200

Scheme 4

indicated by NMR analysis, a single type of allylindium species is generated during the insertion of indium(I) halide to allyl halide and the structure was proposed to be an allylindium(III) dihalide. In comparison with allylindium sesquihalide, one great advantage of using this allylindium diiodide is that all the allyl groups can be fully utilized in subsequent 1,2-addition to carbonyl compounds. In addition, the generated allylindium diiodide exhibited similar reactivity and selectivity as allylin273


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2.3. Nature of Allylindium Reagent

dium sesquihalide. However, two pronounced differences were noticed: the insertion proceeded more efficiently in THF than in DMF and both α- and γ-product were generated when γsubstituted allylic halide such as crotyl iodide was used as substrate. Because of the higher cost of indium(I) halide as compared to indium(0), this method has not been widely adopted for the generation of allylindium reagents. Alternatively, allylindium reagents can be generated by the transmetalation of indium(III) halides with other more reactive organometallic species such as organolithium or organomagnesium reagents (Scheme 5).50 Only one-third equivalent

Knowing the identity of the formed allylindium species in reaction is very important for rational reaction design because the reactivity of different allylindium species may vary considerably.84 Though many studies have been carried out to probe the identity of the allylindium species in allylation reaction, taking advantage of modern techniques such as NMR study, X-ray crystallographic analysis, and mass spectrometry, the real nature of the reactive allylindium species has yet to be fully confirmed. Most of these structures are proposed based on data and information collected indirectly. Here, we will give a thorough overview of the numerous reports relating to determination of the nature of the allylindium reagent, including the more recent advancements. It needs to be mentioned that, very recently, a summarization of previous studies directed toward the determination of the reactive allylindium species formed in indium-mediated allylation has also been reported.142 In 1988, Araki, Ito, and Butsugan38 proposed that, in organic solvents such as DMF and THF, an allylindium sesquihalide (R3In2X3, R = allyl, X = Br or I) may be the real reactive organoindium species formed in the reaction (Scheme 1). Their proposal is based on the following information collected. First, studies of the relationship between the observed yields and ratios of indium/allyl iodide/ketone had shown that the highest experimental yield of 89% was obtained when an optimal ratio of indium/allyl halide/ketone = 2:3:2 was used, indicating that only two-thirds of the allyl groups were consumed in the allylation of carbonyl compounds. Second, when indium was mixed with allyl iodide in DMF, they observed two sets of allylic methylene signals at δ 1.75 and 2.02 ppm with a relative intensity of 2:1 in the 1H NMR spectrum (DMF-d7 as solvent). These findings led them to propose the reactive allylindium species formed in DMF as an allylindium sesquihalides. This proposal is in agreement with results obtained from the insertion of indium into alkyl halide by Gynane and Worrall in 1974.17 Thereafter, the formulation of allylindium sesquihalide (R3In2X3) was generally regarded as the reactive allylindium intermediate in allylation reactions performed in organic solvents. For convenience, in this review we also adopted this formulation as the allylindium species formed in organic solvent, although it may not always be the case in reality. When an indium-mediated allylation was performed in aqueous media, an allylindium(I) was postulated by Chan and Yang to be the reactive intermediate involved in the reaction. In the 1H NMR study conducted by them,153 only one set of newly formed allylic methylene signals located at δ 1.7 ppm was observed after mixing indium with allyl bromide in D2O. They assigned the sole reactive organoindium species observed in the reaction as allylindium(I), in view that it exhibited similar reactivity (toward carbonyl compounds) and shared the same chemical shift (δ 1.7 ppm) as the known allylindium(I) intermediate, which can be prepared from the reaction of diallylmercury with either indium(0) or indium(I) iodide (Scheme 7). Apart from that proposal, Chan also questioned the authenticity of the allylindium sesquihalide, which was speculated to be the reactive allylindium species in organic solvents. During the course of their study, Chan and Yang153 observed that, when the preformed allylindium species (having two sets of allylic methylene signals at δ 1.75 and 2.15 ppm) in DMF was exposed to D2O for 5 min, the signal at δ 2.15 ppm

Scheme 5

of indium(III) halide is required to produce the desired triallylindium compound. Also, diallylindium and monoallylindium reagents can be prepared by adjusting the molar ratio of indium(III) halides and organometallic reagents. The transmetalation of allylstannane with indium(III) halide also provides an easy entry to an allylindium reagent.211,212 Loh and co-workers have also demonstrated that such transmetalation can be carried out in aqueous media with success.213 In addition, recent advancement has shown that reductive transmetalation of π-allylpalladium(II) and π-allylnickel(II) complexes with indium(I) halide or metallic indium(0) provides a new route for the preparation of allylindium reagents.214 Considering that three excellent reviews relating to these topics have been summarized by Marshall211 and Roy,149 these methods will not be included here. Apart from the generation of allylindium reagent by indium insertion into allyl halide, allylindium species also can be accessed from a radical-type conjugate hydroindation of 1,3dienes by dichloroindium hydride (HInCl2, in situ formed by mixing InCl3 with Bu3SnH). As demonstrated by Baba and coworkers, the in situ generated allylindium species reacted with both aldehyde and ketone in a one-pot manner to generate the expected γ-adducts of homoallylic alcohols in generally moderate to good yields within 3 h (Scheme 6).215 In Scheme 6

comparison, better yields were achieved by using sterically less congested 1,3-diene. No allylation product was obtained in the use of cyclohexadiene and 1,4-diphenyl-1,3-butadiene, and mostly a reduction of carbonyl compound occurred under these conditions. Tolerance of the methodology to functional groups like chloride, nitro group, and ester was observed. It is worthy to note that imine can be used as electrophile as well. However, in cases where two diastereomers were generated, the syn/anti diastereoselectivity of the product was not high. Later they found that, in most instances, performing the allylation step for a longer reaction time under refluxing conditions might convert the initially formed γ-adduct into the thermodynamically more stable α-adduct.216 274


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Scheme 7

Scheme 8

disappeared while the signal at δ 1.75 ppm, which was identical to that of allylindium(I), still remained. In addition, when the preformed allylindium species was left overnight, the signal at δ 1.7 ppm was greatly diminished while the signal at δ 2.15 ppm was intensified. On the basis of these observations, Chan and Yang hypothesized that, rather than the formation of a single type of allylindium sesquihalide as suggested by Araki, Ito, and Butsugan, two types of allylindium species were in fact produced in DMF, and one of the species corresponds to allylindium(I). In addition, the allylindium(I) species was transformed into the other allylindium species, which has a characteristic methylene signal at δ 2.15 ppm, after being left overnight. A few years later, Preite and Pérez-Carvajal168 observed an analogous phenomenon in their studies and arrived at the same conclusion as Chan and Yang. In 2007, during the investigation on the indium-mediated allylation of imine in ionic liquid, Chan and co-workers made another attempt to elucidate the reactive allylindium species involved in DMF and ionic liquid.217 It was found that two similar sets of allylic methylene signals at δ 1.75 and 2.02 ppm were also generated in the reaction of indium with allyl bromide in ionic liquid, in which the signal at δ 1.75 ppm was previously assigned to allylindium(I). Moreover, they found that the signal at δ 2.02 ppm might be allylindium(III) dibromide or its dimer, because allylindium(III) dibromide prepared from the insertion of In(I)Br into allyl bromide also displayed the same signal at δ 2.02 ppm, which is also consistent with what Araki et al. had observed in the preparation of allylindium(III) diiodide from the reaction of indium(I) iodide with allyl iodide in THF.210 Hence, they proposed that the two species formed, either in organic solvent or ionic liquid, are allylindium(I) and allylindium(III) dibromide. In addition, the observation that the signal at δ 1.7 ppm was greatly reduced while the signal at δ 2.15 ppm was enhanced upon standing overnight indicated an equilibrium between allylindium(I) and allylindium(III) dibromide. More recently, through X-ray crystallographic analysis, Baba and co-workers studied the allylindium species generated from different methods.46,47 Because the actual organoindium species formed in the reaction were isolated and analyzed by X-ray crystallography, their findings may be more convincing and conclusive. When cinnamyl bromide was treated with indium in THF, 1 H NMR monitoring showed the presence of two types of allylindium species, which is in agreement with what has been observed by other groups. Subsequently they managed to obtain two suitable crystals for X-ray crystallography upon complexing them separately with two different pyridine ligands (L and L′) (Scheme 8).46 X-ray crystallographic analysis indicated the formation of a cinnamylindium(III) dibromide complex 1·2L and a dicinnamylindium(III) bromide complex 2·2L′, both with a five-coordinated indium center. In addition, authenticity of the cinnamylindium(III) dibromide complex

1·2L was further confirmed by the fact that its NMR signals were identical to those of authentic cinnamylindium(III) dibromide, synthesized via transmetalation between tributyl(cinnamyl)stannane and InBr3, followed by complexation with ligand (L). When the two species were treated with aldehyde, it was found that dicinnamylindium(III) bromide 2 reacted preferentially over cinnamylindium(III) dibromide 1. In a similar manner, crystals of allylindium(III) dibromide and diallylindium(III) bromide suitable for X-ray diffraction analysis were also obtained by mixing allyl bromide and indium in THF, followed by complexation with the pyridine ligands (L and L′) (Scheme 9).47 Scheme 9

Most significantly, upon comparing the two 1H NMR spectra obtained by using DMF-d7 and D2O as cosolvent (3:1), Baba and co-workers discovered that the allylindium species formed in water or aqueous medium were essentially the same as the two species formed in organic solvents (such as THF or DMF) (Scheme 10).47 Thus, they suggested that the two allylindium Scheme 10

species formed in aqueous medium were also allylindium(III) dibromide and diallylindium(III) bromide, as opposed to the allylindium(I) species proposed by Chan and Yang. The allylindium(III) dibromide is stable in aqueous media. In comparison, the diallylindium(III) bromide is more reactive and decomposes rapidly in aqueous media to give propene and another reactive allylindium complex with the structure shown in Scheme 11, namely, the allyl(μ-hydroxido)indium species. The structure of this type of allylindium complex was Scheme 11

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isolated. X-ray crystallographic analysis revealed the formation of an allylindium(III) dibromide with two coordinative ligands of acetonitrile and phthalan. However, due to the bulky substituent at the indium center, the nucleophilicity of the allylindium species toward aldehyde was greatly reduced. More recently, the same group also reported the X-ray crystallographic analysis of two interesting butenylindium compounds prepared from the transmetalation between cyclopropylmethylstannane and indium halides.52 On the basis of the above studies from several groups, we surmised that allylindium(III) dihalide (RInX 2 ) and diallylindium(III) halide (R2InX), instead of a combined formulation of allylindium sesquihalide (R3In2X3), are most probably the active allylindium species formed during allylation reactions both in organic solvents and in aqueous media, although in aqueous media, diallylindium(III) halide (R2InX) might decompose, leading to the coexistence of an allyl(μhydroxido)indium species. However, a possible transient formation of an allylindium(I) cannot be precluded.

confirmed by X-ray crystallographic analysis of the analogous cinnamyl(μ-alkoxido)indium compound, generated by alcoholysis of dicinnamylindium(III) bromide, which also exhibited considerable reactivity toward allylation with benzaldehyde in 47% yield (Scheme 12). This phenomenon, as well as the Scheme 12

aforementioned use of DMF-d7 and D2O (3:1) as both reaction and NMR solvents, might explain why only one set of peaks was detected in the previous NMR study by Chan and Yang. Very recently, a new method attempting at determination of the allylindium species in DMF, THF, and water, based on a combination of electrospray-ionization mass spectrometry, temperature-dependent 1H NMR spectroscopy, and electrical conductivity measurements, was reported by Koszinowski.218 The results obtained suggested the presence of allylindium(III) species, which undergo solvolytic heterolytic dissociation to yield ions such as InR2(solv)+ and InRX3− (Scheme 13).

2.4. Addition to Carbonyl Compound

2.4.1. Different Solvent Media. As demonstrated by Araki, Ito, and Butsugan in 1988,38 the insertion of powdered indium(0) into allyl bromide or iodide occurs efficiently in DMF at room temperature and the in situ-generated allylindium reagent spontaneously reacts with various carbonyl compounds to give homoallylic alcohols in moderate to good yields (Scheme 15). Other polar solvents such as THF and

Scheme 13

Scheme 15

Another study conducted by Bowyer and co-workers using a photomicrographic technique to measure the reaction rates of allyl halide at the indium surface suggested that the reactivity was found to be diffusion-controlled in aqueous solution.219 Moreover, an NMR study also showed that indium reacted with the allyl halide in a ratio of 2:3 in aqueous media, likely pointing to the generation of an allylindium(III) compound under the conditions. More recently, the same group also used photomicroscopy with three new strategies to measure the heterogeneous reaction rates of allyl halides with indium and found that their reactions proceed under mass transport control.220 The structure of the allylindium intermediate generated from the transmetalation of allylstannane with indium(III) halide has also been determined by X-ray crystallographic analysis from Baba’s group.51 As shown in Scheme 14, after exposure of allylstannane to InBr3 in acetonitrile followed by complexing with phthalan, a crystal appropriate for X-ray analysis was

CH3CN can be used as well, but no reaction took place in less polar or nonpolar solvents such as hexane, benzene, and CH2Cl2.221 In contrast, allyl chloride exhibited lower reactivity under the same conditions. In comparison with allylmagnesium and allyllithium compounds, allylindium reagents exhibit relatively lower basicity and nucleophilicity. Hence, a Wurtztype side-reaction, which often plagues the preparation of allylmagnesium and allyllithium species, is not detected in the preparation of allylindium reagents. In addition, ester functionality present in the carbonyl substrate is compatible with the mild reaction conditions. Also, substrates with labile protons such as ethyl acetoacetate and salicylaldehyde also can be successfully employed in the protocol. Especially noteworthy is that, with regard to α,β-unsaturated carbonyl substrate, the allyl group added exclusively at the carbonyl group in a 1,2addition manner, with no 1,4-addition product observed. In 1991, Li and Chan39 reported the first instance of carrying out an indium-mediated allylation reaction in an aqueous medium. They found that the allylation of carbonyl compounds worked equally well in water222 to give the expected products in satisfactory yields (Scheme 16). The reaction can be performed at room temperature without the need of an inert atmosphere,

Scheme 14

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advantage of this method is that byproducts arising from homocoupling of either aldehyde or allyl halide were not observed. Two consecutive [4 + 2] processes have been tentatively proposed by the authors to account for the generation of the final product, where the formation of an allylindium(I) species from allyl halide and indium and a sixmembered transition state involving an allylindium(II) species has been surmised. Later, a similar study under solvent-free conditions by using different metals as reaction mediators (including In, Bi, Cu, and Zn) was reported by Andrews, Peatt, and Ratson, and again indium was found to be superior to other metals.59 In addition to the above solvent media, supercritical CO2 can be utilized as a reaction medium as well. Li and co-workers reported that homoallylic alcohols can be produced in 38−82% yields under these conditions.228 This variant provides a clean method for the synthesis of homoallylic alcohols, because liquid CO2 can be easily removed from the reaction mixture by depressurization. 2.4.2. Versatility of Carbonyl Compound and Related Derivative. The relatively low nucleophilicity of allylindium reagent, as well as its compatibility with various functional groups, imparts unique reactivity toward various carbonyl compounds and related derivatives, which is somewhat difficult to achieve using other more reactive organometallic reagents. Owing to the mildness of the allylindium reagent, compounds containing a labile Fe(CO)3-complexed pentadienyl group can be allylated.61 For example, reaction of such a substrate with in situ-generated allylindium reagent afforded the corresponding homoallylic alcohol in 85% yield (Scheme 18).

Scheme 16

and substrate containing a hydroxy group can be used without preprotection. Thus, water-soluble carbohydrates can be directly used without prederivation, which further reinforces the synthetic value of the allylindium reagent. Carbonyl compounds containing an acid-sensitive acetal group can also be allylated without affecting the acetal group as well. Compared to allylation using zinc and tin where acid catalysts, heat, or ultrasonication were often needed,223 the indiummediated allylation took place effectively even without any special activation. Most significantly, in most cases, better yields were obtained when indium was used in place of zinc or tin. Furthermore, the allylation with indium proceeded cleanly in water: byproducts including alcohol and pinacol, resulting from metal-mediated reduction and homocoupling of the carbonyl compound, often encountered in allylation using zinc, tin, or magnesium as metallic reagents, are altogether absent in indium-mediated allylation reaction. Notably, by adjusting the ratio of THF/H2O (4:1), the reaction time can be greatly reduced to within 1 h while still maintaining its high reaction performance.224 Allylation reaction using allylindium reagent can be achieved in ionic liquid as well, as described by Gordon and Ritchie.225 The use of the ionic liquid, [bmim]BF4, as reaction medium gave comparable performance compared to the same reaction performed in an organic solvent (Scheme 17). Their

Scheme 18

Scheme 17 In sharp contrast, no desired product was observed when the more reactive allylmagnesium bromide was utilized as the allylating reagent. The mildness of allylindium species also made possible its reaction with resin-bound aldehydes possessing base-labile linkers, when the reactions were carried out in aqueous THF under ultrasonication. The usefulness of the method was further demonstrated through the synthesis of amino alcohols.229 A one-pot, sequential double allylation of dicarboxaldehyde with two different allyl groups was developed by Baba and coworkers, leading to unsymmetrical bis-homoallylic alcohols A in acceptable yields (Scheme 19).159 The formation of byproduct B was detected, which may be formed due to considerable retro-allylation of the first-formed monoallylated intermediate, when a highly reactive allylindium species was introduced in the next step. This difficulty can be overcome by quenching the monoallylated indium homoallylic alkoxide species with HOAc, prior to introduction of the second allyl group. It should be noted that the presence of HOAc does not retard the second allylation because indium-promoted allylation is well-known to tolerate acidic conditions and its presence might in fact accelerate the reaction. Recently, the functionalization of allene has aroused considerable attention.230 Ma and co-workers described an indium-mediated allylation of 2,3-allenal (Scheme 20).63

investigations showed that an aqueous workup was essential in order to achieve good isolated yield of the desired product, which may serve to quench the initially formed indium alkoxide intermediate, so as to release the desired homoallylic alcohol product. When 2-methoxycyclohexanone was used as substrate, a higher diastereoselectivity (syn/anti = 18.6:1) was obtained in [bmim]BF4 than in pure water or aqueous THF. Almost simultaneously, Chan’s group reported that allylation of carbonyl compound in [bmim]BF4 mediated by Zn, Sn, or In proceeded with high efficiency, while the use of Sn led to the best performance.226 Li and co-workers had shown that indium-mediated allylation also proceeded well under solvent-free conditions.227 While under identical conditions, the use of zinc or tin as mediating agent led to relatively low yields of the products. Another 277


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(NMF) and dimethylsulfoxide (DMSO) in the presence of ultrasonication (up to 35% yield). Indium-mediated allylation of β-chloro- or β-alkoxyvinylaldehydes in the presence of sodium iodide produced the desired homoallylic alcohols of 1-chloro- or 1-alkoxyhexa-1,5-diene-3-ol in good yields (Scheme 22).160 Interestingly, in cases where β-

Scheme 19

Scheme 22

bromovinylaldehydes were used as substrates, the obtained homoallylic alcohols of 1-bromohexa-1,5-dien-3-ols can be further manipulated into cyclopentenones by means of a palladium-catalyzed oxidative cyclization.232 Similarly, a fast entry to the synthesis of carbo-annulated quinolines was accomplished via an indium-mediated allylation of 2-chloro-3-formylquinoline in water followed by a palladiumcatalyzed intramolecular cyclization of alkene (Scheme 23).108 An analogous allylation using zinc as reaction mediator in a mixture of THF and aq. NH4Cl only led to moderate yields. In addition, they also developed an efficient method for the construction of cis-4-hydroxy-2-iodomethylpyrano[2,3-b]quinoline via an aqueous-based indium-mediated allylation of 3-formyl-2-quinolones followed by an intramolecular electrophilic cyclization of the resultant 3-homoallyl-2-quinolones with iodine (Scheme 24).233 A simultaneous indium-mediated reduction−allylation reaction of nitro and formyl groups of 2-nitrobenzaldehydes in aqueous HCl took place to give anilinyl homoallylic alcohols in acceptable yields (Scheme 25).234 The resultant homoallylic alcohols could be subsequently converted into dihydroindolones and dihydroquinolones via a three-step transformation involving amino group protection, PCC-mediated oxidation, and base-promoted intramolecular cyclization. When N-alkyl indole-3-carboxaldehydes and N-alkyl pyrrole3-carboxaldehydes were treated with indium (2 equiv) and allyl bromide (3 equiv) in THF/H2O, an abnormal double allyl addition occurred, providing 3-(1,6-diene-4-yl) indole and pyrrole derivatives in acceptable yields (Scheme 26).235 Kumar and co-workers claimed that the reaction proceeded through an indium alkoxide intermediate rather than a carbocation, because the reaction also worked well in organic solvent such as dry THF or EtOH. The only exception to this trend is the use of Ncarboxy indole-3-carboxaldehyde possessing an electron-withdrawing group (R = COOEt). The substrate only underwent a normal monoallylation at formyl group, a reflection of the electronic factors which governed the different outcomes of the reactions. Interestingly, in the presence of other nucleophiles, a threecomponent coupling of 1H-indole-3-carboxaldehydes, allyl bromide, and various nucleophiles proceeded in aqueous THF to furnish functionalized indolylbutenes (Scheme 27).236 When 5-formyluracils and 4-formylpyrazoles were subjected to indium-mediated allylation reactions in the presence of BF3·OEt2 (1 equiv), various 1,3-diene-substituted heterocycles were produced in satisfactory yields (Scheme 28).237 By combining an L-proline-catalyzed direct organocatalytic asymmetric Mannich-type reaction with an indium-mediated

Scheme 20

Optimal results were obtained when the reactions were performed in a mixed medium of THF with saturated aqueous NH4Cl rather than in pure water, chemoselectively providing moderate to good yields of synthetically useful 1,5,6-alkatrien-4ols. No addition to the C−C double bond of the allenal was observed under the mild reaction conditions. Zinc also can be used as reaction mediator, but preactivation of zinc is critical for achieving good yields. In most cases, indium exhibited better performance than activated zinc. When propargyl aldehyde was treated with allylindium reagent in water, exclusive 1,2-addition at the aldehyde occurred to give product A (Scheme 21).231 Of special interest Scheme 21

is the finding that, when the reaction was carried out in an organic solvent such as THF or DMF, formation of differing amounts of compound B, seemingly resulting from a direct 1,4addition of allyl group to propargyl aldehyde, was also isolated. In actual fact the reaction proceeded, as verified by Mitzel and co-workers, through a [3,3]-oxy-Cope rearrangement of an indium alkoxide to give an allenolate. Attempts to increase the yield of the product B had only met with modest success, by carrying out the reaction in a mixture of N-methylformamide 278


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Scheme 23

Scheme 24

Scheme 28

Scheme 25

allylation performed in aqueous media, an efficient synthesis of highly functionalized lactones was realized in good yields (64− 77%, Scheme 29).238 However, the chirality installed during the Scheme 29

first step almost had no influence on the second step, thus resulting in poor diastereoselectivity in the subsequent allylation reaction (1:1−2:1 dr). In situ formation of aldehyde from the oxidation of alcohol followed by one-pot indium-mediated allylation also provides an alternative method for the synthesis of homoallylic alcohol. Recently, Yadav and co-workers developed such a one-pot sequence by using chloramines-T (sodium salt of Nchlorotosylamide) as oxidant in the presence of a catalytic amount of FeCl3 in CH2Cl2, giving rise to homoallylic alcohols in good to excellent yields (Scheme 30).239 It is noteworthy

Scheme 26

Scheme 30

Scheme 27 that the generated byproduct of TsNH2 (from the reduction of chloramines-T) may react with the in situ-formed aldehydes to give intermediates of N-tosylimines in the presence of 4 Å molecular sieve under refluxing; the thus-formed N-tosylimines subsequently underwent one-pot indium-mediated allylation to produce homoallylic amines in 60−80% yields. Later, a similar one-pot, two-step sequence for the synthesis of homoallylic alcohols via a galactose oxidase-mediated chemo-enzymatic oxidation of benzyl and cinnamyl alcohols to the corresponding 279


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aldehydes followed by an allylation using allylindium or allylborane also was developed (Scheme 31).240

Scheme 34

Scheme 31

In addition to α,β-unsaturated aldehyde, α,β-unsaturated ketone is also a suitable candidate to undergo indium-mediated allylation under appropriate conditions. When the allylations using allyl iodide were performed in DMF or THF in the presence of a stoichiometric amount of InCl3 (1 equiv), the allyl group only attacked the ketone functionality of α,βunsaturated ketone to give 1,2-addition products in 30−99% yields (Scheme 32).204 An attempt to run the reaction in aqueous media was proven unsuccessful.

Scheme 35

In 2005, Mal and co-workers investigated the allylation of quinol ethers and quinone monoketals in DMF. Interestingly, only ortho-allylated phenol was afforded (Scheme 36).165 The

Scheme 32

Scheme 36

Intriguingly, Lloyd-Jones and co-workers unexpectedly discovered that homoallyl-substituted vinylcyclopropanes can be prepared by reacting allylindium reagents with α,βunsaturated ketones and aldehydes (Scheme 33).241 An unusual Scheme 33

reaction was proposed to proceed via the 1,2-addition of allylindium to the carbonyl group followed by an arrangement involving displacement of the methoxy group with concomitant migration of the allyl group. Difluoroacetyltrialkylsilanes can be allylated by allyl bromide in aqueous medium as well to provide homoallylic alcohols exclusively (Scheme 37).75 But in the case of γ-substituted allyl

aerobic acidic workup was the key to achieving this transformation, and the addition of LiBr improved the isolated yield of the product. Although poor regioselectivity was observed in the use of allyl halide, good to perfect regioselectivity was obtained when crotyl halide was employed instead, favoring selective formation of the cis-cyclopropane isomer. By taking advantage of Grubbs′ catalyst-mediated ring-closing metathesis (RCM), the product can be further elaborated into a bicyclic norcarene. An enantioselective version of the indium-mediated homoallyl-cyclopropanation of dibenzylideneacetone, by using enantiomerically pure (S)-methyl mandelate as chiral ligand, was also successfully developed with useful enantiopurity (88% ee) and applied to the synthesis of a norcarene unit without loss of enantiopurity (Scheme 34). Allylation of a range of quinones by allylindium sesquihalides was also studied by Butsugan and co-workers.242 For instance, the reaction of p-benzoquinone with allylindium reagent proceeded smoothly at −45 °C to give allylquinol in almost quantitative yield. After oxidation with silver oxide, the corresponding allylated quinone was obtained in 91% yield (Scheme 35). The sequence was proposed to proceed via a 1,2addition of allylindium reagent to the carbonyl group, followed by a [3,3]-sigmatropic rearrangement. Later, a similar study was conducted by Ray and co-workers.243

Scheme 37

halide, no desired product was obtained when indium was used as activator, while zinc served as an effective substitute for indium. A possible Brook rearrangement that involves migration of the silyl group to the in situ-generated oxyanion was not detected. In comparison, the addition of organomagnesium244 or organolithium reagents245 to trifluorinated acylsilanes leads to the formation of silyl enol ethers via a Brook rearrangement followed by subsequent defluorination (Scheme 38). 280


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amount of allyl bromide used (Scheme 41).249 The same behavior was observed when the reaction conditions were

Scheme 38

Scheme 41 The indium-mediated allylation had also been employed to prepare α-hydroxylketone, starting from 1,2-diketones. As demonstrated by Nair et al.,60 after treatment of 1,2-diketone with 1.55 equiv of allyl bromide, 1.05 equiv of indium, and 1.55 equiv of NaI in DMF, only the monoallylated α-hydroxylketone product was generated in excellent yield within several minutes (Scheme 39). The presence of NaI was essential for the success Scheme 39 applied to glyoxals 4 and bishydrazones 5. Furthermore, bisfunctionalized 1,2-diols can be furnished in a one-pot fashion by a sequential nucleophilic addition of an alkyllithium compound to the ketone functionality of the glyoxal monohydrazone followed by an indium-mediated allylation of the resulting hydrazone (Scheme 42).

of the reaction. In certain cases, the utilization of ultrasonication irradiation also exerted a positive effect on the activation of some less reactive substrates. Lee et al. reported that similar indium-mediated allylations using 1.5 equiv of allyl bromide but performed in aqueous THF led to a mixture of mono- and double-allylated products,246 whereas in another case Kumar and co-workers found that the similar reactions employing 1,2-dicarbonyl compounds of arylglyoxals performed in aqueous media in the presence of 3 equiv of allyl bromide resulted in the exclusive double allylation of both carbonyl groups of the substrates.247 An elegant strategy for the synthesis of 1,6-dicarbonyl compounds starting from 1,2-dicarbonyl compounds was established by Mendez-Andino and Paquette (Scheme 40).248

Scheme 42

Similarly, Lee et al. proved that α-ketoesters also served as efficient electrophiles in undergoing indium-mediated allylation in aqueous media, in most cases with the addition of diluted aq. HCl as reaction additive (Scheme 43).246,250 Huang and coworkers also utilized the indium-mediated allylation of αketoesters as a key step in the synthesis of homocitric acid lactone and trimethyl per-homocitrate.251

Scheme 40

Scheme 43

The strategy involves a sequential indium-mediated double allylation of 1,2-dicarbonyl compound, ring-closing metathesis using Grubbs′ catalyst (second generation), followed by a criegee-type oxidative cleavage of the resultant diol by Pb(OAc)4 (with or without prior hydrogenation). It should be mentioned here that, as compared to the similar reaction shown previously, different ratios of substrates and reaction time might be the key factors in governing the varied reaction outcomes. In addition to 1,2-dicarbonyl compounds, glyoxal monohydrazones and bishydrazones also can be introduced as 1,2dicarbonyl compound equivalents. When glyoxal monohydrazones 3 were mixed with allyl bromide and indium in water, a reaction occurred to give bis-allylated vicinal 1,2-diols in 94% yields with 1:1 diastereomeric ratio (dr), regardless of the

The synthesis of oxindole is of particular interest due to the biological activities associated with some members of this family, as well as the fact that they are immediate precursors to indoles. Starting from 2,3-indolinediones (isatins), the addition of allylindium reagent in the presence of NaI in DMF gave the desired 3-substituted 3-hydroxyoxindoles in satisfactory yields ranging between 65% and 95%.154 Subsequently, Alcaide et al. reported that the reaction can also be carried out in aqueous media (Scheme 44).199 Their findings disclosed that good to excellent yields of 3-substituted 3-hydroxyoxindoles were obtained when indium-mediated allylations were operated using hafnium(IV) chloride (HfCl4) as an additive in aqueous THF. Polyethylene glycol (PEG-400) was also proven to be a 281


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Scheme 44

Scheme 47

Interestingly, when 4-ketoester of ethyl levulinate was subjected to indium-mediated allylation under identical conditions, γ-butyrolactone was eventually produced as a consequence of a further lactonization of the first formed allylated intermediate (Scheme 48).246

suitable solvent for the allylation of isatins.107 Under the established conditions, indium was found to be superior to other metals (such as zinc and tin) in mediating the allylation, leading to the allylated products with a high level of chemical yields (93−99% yields). The indium-mediated allylation worked equally well for acyl phosphonates by judicious selection of reaction solvent and additive. Through fine-tuning of the reaction conditions, it was found that the ketone functionality of acyl phosphonate can be allylated in THF in the presence of acetic acid, giving tertiary αhydroxy phosphonates in high yields (Scheme 45).177 The

Scheme 48

Scheme 45 Indium-mediated allylation in water can be extended to acid chloride as well, and the work was conducted by Yadav and coworkers. Various acid chlorides were allylated in the presence of allyl bromides and indium in DMF/H2O to afford β,γunsaturated ketones in 55−85% yields (Scheme 49).253 No isomerization of the resulting product to conjugated α,βunsaturated ketone was observed. In addition, no double allylation occurred under the conditions employed.

addition of acetic acid is crucial; otherwise it results in poor isolated yield of the desired product. In addition, another advantage of using this mild allylindium reagent is that substitution of the phosphonate functionality by the allyl group is inhibited. β-Keto phosphonates are useful synthons for organic synthesis. However, the presence of relatively acidic active methylene protons in β-keto phosphonate poses a challenge for the nucleophilic addition of reactive allylmetallic reagent to the carbonyl group.252 In contrast, the mild reaction conditions involved in indium-mediated allylation enable β-keto phosphonate to be allylated effectively. Various β-hydroxy phosphonates can be readily produced when the corresponding β-keto phosphonates were subjected to coupling with allylindium sesquihalides in THF (Scheme 46).74 Functionalities such as phosphonate, ester, nitro, and furan moiety were found to be well-tolerated by the mild reaction conditions.

Scheme 49

In a similar fashion, the cyano group also served as a good leaving group when acyl cyanide was subjected to indiummediated allylation. For example, acyl cyanides reacted with allyl halides in aqueous media to afford β,γ-unsaturated ketones in moderate to good yields under mild conditions (Scheme 50).254 In addition, no further attack of the allylindium reagent at the carbonyl group was observed under the stated conditions. In addition, Yadav et al. had shown that allyl bromohydrin can be obtained through the reaction of α-diazoketone with in situ-generated allylindium reagent, followed by substitution of the diazo group with bromide (Scheme 51).255 No sidereaction such as Wolff rearrangement or carbene dimerization was detected under optimized conditions. Furthermore, the

Scheme 46

Scheme 50 Li and Lu reported that enolizable β-ketoesters underwent efficient indium-promoted carbonyl allylation in water-containing solvents to afford β-hydroxyesters in good yields (Scheme 47).62 1,3-Diketone can be monoallylated as well, but along with generation of the bis-allylated products. The use of tin as reaction promoter led to decreased performance. 282


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A very recent work performed by Kim and co-workers demonstrated that 1,3,5-triketone can be selectively monoallylated even in the presence of 3 equiv of allyl bromide and 2 equiv of indium, giving rise to the corresponding homoallylic alcohol in good yield (Scheme 55).258 A transition state

Scheme 51

Scheme 55 reactions proceeded with comparable efficiency by using activated zinc as reaction promoter. When α-chlorocarbonyl compounds were treated with allyl bromides (1.5 equiv) in aqueous THF in the presence of indium, the corresponding homoallylic chlorohydrins could be obtained in varying yields, depending on both the substituents at the carbon bearing chlorine and the allyl bromides used (Scheme 52).256a The indium-mediated dehalogenation of αScheme 52

involving a chelation of allylindium with the oxygen atom of the carbonyl at C-3 position and additional intramolecular hydrogen bonding was proposed for the selective monoallylation achieved. The thus-formed product can be efficiently transformed into 2,3-dihydro-4H-pyran-4-one via a dehydrative cyclization upon exposure to acid catalysis. Another interesting example is the reaction of 1,5-diketone with methallyl bromide under similar conditions (Scheme 56). The monoallylated

chlorocarbonyl compounds presented itself as a major sidereaction. The homoallylic chlorohydrins could be easily converted into synthetically useful epoxides in the presence of an appropriate base. A similar manner was observed in the allylation of α,α-dichloroketones in THF where exclusive allylations at the carbonyl groups occurred to give the corresponding homoallylic alcohols in good yields (Scheme 53).256b Notably, no chloride displacement or elimination was observed under the present conditions.

Scheme 56

Scheme 53

In another study, Yadav et al. showed that the allylation of aryl-substituted α-chlorocarbonyl compounds proceeded in a totally different way to give vic-diallylated products (Scheme 54).257 This protocol was performed in THF by using 2.5 equiv Scheme 54 product having a methallyl moiety can be selectively converted into either 3,4-dihydro-2H-[1,4]oxazine or 9-oxa-3azabicyclo[3.3.1]non-6-ene under judiciously selected conditions in the presence of protic acid. An acid-catalyzed oxoniumene reaction is presumably responsible for the formation of the latter product. Allylindium sesquihalide had also been utilized in the allylation of cyclic acid anhydrides such as phathalic anhydride to give gem-diallyl esters (Scheme 57). In comparison, when γ,γ-disubstituted allyl bromide was used, presumably due to steric hindrance, monoallylated product was obtained solely. Cyclic acid anhydride like benzoic anhydride reacted poorly

of allyl bromide, which might account for the different outcomes from above case. Phenacyl azide was also bis-allylated in a similar manner under the same conditions. However, when α-chlorocarbonyl compound bearing a strong electron-withdrawing group such as NO2 or F in the aryl moiety was used, monoallylated product at the carbonyl group was isolated as the major product. 283


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Scheme 57

Scheme 59

Scheme 60 under identical conditions.259 Cyclic imides also reacted with allyl halides under similar conditions, furnishing diverse products depending on the degree of substitution of the allyl halides used. By employing gem-diallyl esters as synthetic intermediates derived from the indium-mediated allylation of cyclic anhydrides, a variety of spirolactones were conveniently accessed via ring-closing olefin metathesis (RCM).260 2-Pyridyl carboxylate was also demonstrated to be one of the few reactive esters capable of undergoing indium-mediated allylation in water (Scheme 58).173 Intriguingly, when simple

lective synthesis of β,γ-unsaturated ketones, and its synthetic utility was proven through the synthesis of artemesia ketone in 65% yield. An indium-mediated allylation of iodomaleimide was employed for the total synthesis of Lucilactaene. The allylation occurred selectively at the C5-carbonyl distal to the iodide in 81% yield, by performing the reaction in DMF at −15 °C (Scheme 61).262

Scheme 58

Scheme 61

allyl halide was used, 2-pyridyl carboxylate underwent a double allylation leading to a predominant formation of bis-allylation product, whereas a preferential monoallylation of 2-pyridyl carboxylate occurred with the use of γ-substituted allyl halide (such as crotyl bromide and cinnamyl bromide) because of steric hindrance, giving rise to the corresponding ketone as the major product. In contrast, substrate like 3-pyridyl or 4-pyridyl carboxylate cannot react under these conditions, suggesting a possible chelation among allylindium, carbonyl group, and its neighboring nitrogen atom from the use of 2-pyridyl carboxylate. Indium-mediated allylations of allyl bromide with acyloyl imidazoles in water gave the corresponding tertiary alcohols or ketones depending on the nature and structure of the substrates used.261 Normally, simple alkyl and aryl acyloyl imidazoles afforded predominantly tertiary alcohols rather than ketones, indicating that the in situ-generated alkyl and aryl ketone rapidly undergoes a second allylation reaction (Scheme 59). But by using the sterically congested tert-butyl acyl imidazole as substrate, the reaction can be arrested after the first step to afford the corresponding ketone as the major product. Interestingly, when acyloyl pyrazole was selected as substrate, a ketone was obtained as the sole product without undergoing a second allylation (Scheme 60). The startling selectivity was attributed to the chelating ability of the second nitrogen of the pyrazole ring, which might help to stabilize the allylated intermediate formed. The reaction provides a facile regiose-

Despite extensive studies on allylations using carbonyl compounds as electrophiles, hemiacetal as a synthetic equivalent of carbonyl compound can also be allylated in a similar fashion. Loh et al. reported that both trifluoroacetaldehyde and its ethyl hemiacetal were suitable candidates for the In- or Sn/InCl3-promoted allylation in water, providing an easy entry to a wide variety of trifluoromethylated carbinols (Scheme 62).263,264 Later, while exploring the synthesis of Scheme 62

various α-trifluoromethylated oxygenated heterocycles, Billard’s group also investigated the same reaction. Their findings revealed that DMF was superior to H2O as a reaction medium. For instance, substrates such as cinnamyl bromide, which performed poorly in Loh’s conditions in water, proceeded well in DMF to give the product in 90% yield with 90:10 anti/syn selectivity (Scheme 63).265 Acetals and ketals, as aldehyde and ketone equivalents, can also undergo sequential hydrolysis and indium-mediated allylation with various allyl halides in aqueous THF to provide 284


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thalide can also be allylated by indium in the presence of 1 equiv of acetic acid in THF to give the corresponding allylphthalides in excellent yields (Scheme 68).184 The use of

Scheme 63

Scheme 68

the corresponding homoallylic alcohols in moderate to good yields (Scheme 64).266 The reaction worked well with aryl and Scheme 64

acetic acid considerably contributed to the reaction rate and thus shortened the reaction time. In addition, the reaction can also be performed in aqueous THF with equal ease, although in relatively slow reaction rate. In addition to the various carbonyl electrophiles that can be used for indium-mediated allylation, ninhydrin and alloxan are also susceptible to indium-mediated allylation in the presence of NaI in DMF.166 However, the production of a mixture of different types of adducts make the protocol somewhat less attractive for organic synthesis. Finally, allylindium reagent, owing to its mildness, wide functional group tolerance, and its ability to survive in aqueous media, also entailed its use in the functionalization of peptide, protein,269 and moenomycin analogues (Scheme 69).270

conjugated acetals, as well as ketals. In comparison, aliphatic acetal showed poor reactivity. Thus, a chemoselective allylation of aryl acetal or ketal can be achieved in the presence of an aliphatic acetal (Scheme 65). Scheme 65

Scheme 69

gem-Diacetates were also proven to be suitable electrophiles capable of undergoing indium-mediated allylation in aqueous media, leading to the corresponding homoallylic acetates in 51−88% yields (Scheme 66).267 An alternative one-pot method Scheme 66

for the synthesis of homoallylic acetates was also reported by stirring a mixture of aldehyde, allyl bromide, and indium in THF in the coexistence of acyl chloride or anhydride.268 Mucohalic acid, which predominantly exists as a lactone, is in equilibrium with a free aldehyde form via a ring-opening process. Thus, mucohalic acids also can undergo indiummediated allylation reactions in aqueous THF with the delivery of γ-allylic α,β-unsaturated γ-butyrolactones in good to excellent yields (Scheme 67).208 Analogously, 3-hydroxylph-

Although it is still at its early stage, it is believed that more and more such application of indium-mediated reactions in biological chemistry will be seen in the near future. 2.4.3. Versatility of Allyl Substrate. Great versatility of allylic compounds used as substrates in indium-mediated reactions is also well demonstrated in the literature. Kim and co-workers discovered that less reactive allyl chloride can be used as an effective allylating agent in water as well (Scheme 70).173 Simply by carrying out the allylation of aldehyde either in a cosolvent of tBuOH/H2O or under ultrasonication, a greatly improved yield was obtained in either one or both cases. The same trend was also displayed in the use of ketone as substrate. As previously mentioned, nanosize indium169 and indium−boron amorphous alloy170 also allowed the use of less reactive allyl chloride. With the addition of an equimolar amount of lithium iodide, less reactive allyl phosphate can also be used to give a moderate yield of the corresponding homoallylic alcohol (Scheme 71).38

Scheme 67

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by an intramolecular silyl-Prins cyclization promoted by indium halide formed in the allylation step. Later, an analogous one-pot strategy was applied by the same group to the synthesis of cis-2,6-disubstituted tetrahydropyrans by reacting 3-iodo-2-[(trimethylsilyl)-methyl]propene with two different sequentially added aldehydes in the presence of indium (Scheme 74).273 The authors suggested that a possible

Scheme 70

Scheme 74 Scheme 71

While exploring the synthesis of 2-(2-hydroxyethyl)allylsilane, an important intermediate toward the synthesis of polycyclic natural products, Remuson et al. studied the allylation reaction with 3-iodo-2-(trimethylsilylmethyl)propene as substrate.271 By employing indium as a reaction mediator in DMF, the allylation worked well with various carbonyl compounds, providing 2-(2-hydroxyethyl)allylsilanes in moderate to good yields (Scheme 72). Both aliphatic and aromatic

formation of InI during the initial allylation step in aqueous media acted as a promoter for subsequent intermolecular silylPrins cyclization of the in situ-generated trimethylsilyl (TMS)substituted homoallylic alcohol with a second added aldehyde (R2CHO). The utility of this strategy was further demonstrated by a short synthesis of (±)-Centrolobine. Chan and Lee had also shown that α-(bromomethyl)acrylic acid bearing a free carboxyl functionality directly reacted with carbonyl compounds in water, in the presence of indium to give the corresponding γ-hydroxy-α-methylene carboxylic acids in good yields (Scheme 75).274 Similarly, 4-bromocrotonic acid

Scheme 72

Scheme 75

aldehydes bearing hydroxy groups were proven to be good candidates for the reaction. In addition, a satisfactory yield of 71% was afforded even when the less reactive acetophenone was used as substrate. Recently, an interesting cascade reaction involving 1,4- or 1,5-dicarbonyl compound and 3-iodo-2-[(trimethylsilyl)methyl]propene was developed for the synthesis of sevenand eight-membered oxa-bridged carbocycles by Minehan and co-workers (Scheme 73).272 The reactions proceeded well in the presence of indium in aqueous media to generate the aforementioned carbocycles in moderate to good yields. The reaction was suggested to proceed through an indium-mediated allylation of one carbonyl of the dicarbonyl compound followed

reacted with various carbonyl compounds in the same fashion in solvent such as methanol, water, tetrahydrofuran, and ionic liquid [bmim]BF4, leading to the desired products in 21−99% yields (Scheme 76).275

Scheme 73

α-Methylene-γ-butyrolactone moiety is widely featured in a variety of natural products that exhibit interesting biological properties. By mimicking the above conditions, Yus’s group found that α-methylene-γ-butyrolactone can be readily accessed from the indium-mediated coupling of aldehyde with unprotected 2-(bromomethyl)acrylic acid in THF/H2O (Scheme 77).276a,b Acidic workup with aqueous HCl is necessary to achieve complete lactonization. Later, this method was utilized by Kang and co-workers in the synthesis of both racemic and enantiopure forms of γ-hydroxy-α-keto acids.276c A reaction sequence involving an indium-mediated allylation of aldehyde, followed by a DBU-catalyzed isomerization of alkene, enabled the synthesis of (E)-β-methyl Baylis−Hillman adduct with high selectivity (>92:8 E/Z, Scheme 78).187

Scheme 76

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Scheme 77

Scheme 81

Scheme 78

ans,281 difluoromethylenated massoialactone,282 4,4-difluoroglycosides,283 difluorinated sugar nucleosides,284 and (Z)fluoroalkene dipeptide isosteres285 were demonstrated by the groups of Percy, Qing, and Taguchi. The allylation of aldehydes by using two variants of the above 1-bromo-1,1-difluoropropene, namely, (E)-(3-bromo-3,3-difluoroprop-1-enyl)trimethylsilane and 1,1,3-tribromo-3,3-difluoroprop-1-ene, were also successfully achieved by employing lithium iodide as reaction additive, allowing the introduction of CF2 substituent into the organic molecule. As documented by Qing and Wan, the reactions with the former allylating agent occurred efficiently with the retention of the initial geometry of the alkene (Scheme 82).167 Interestingly, the use of the latter tribromide substrate led to the complete reduction of the two vinyl carbon−bromide bonds (Scheme 83).

Various aldehydes were allylated by allyl bromides in aqueous THF in 17−85% yields. The presence of HCl appeared to accelerate the reaction, thus leading to reduced reaction times. Indium-mediated allylation of fluorous-tagged allyl halide with aldehyde can be performed in water as well (Scheme 79).277 Various fluorine-containing homoallylic alcohols can be Scheme 79

Scheme 82

obtained in moderate to good yields. Of special interest is that pure fluorous-tagged product can be obtained by a simple filtration of the reaction mixture through a short plug of fluorous silica gel, using acetone and water as eluant. Upon treatment of the resultant esters with base, α-methylene-γbutyrolactones were generated in high yields. Cyano-containing 3-bromo-1-cyano-1-propene was also found to be an effective allylating agent. Coupling of this reagent with various aldehydes in the presence of indium in water provided α-cyano-β-ethylenic secondary alcohols in moderate yields (Scheme 80).278

Scheme 83

When oxindolidino allyl bromide was treated with 40% aqueous formaldehyde and indium in DMF, a Barbier-type allylation occurred to deliver 2-oxindolidino homoallylic alcohol as the major product (Scheme 84).286 Upon exposure of the resulting hydroxyester to p-toluenesulfonic acid (PTSA)catalyzed lactonization, a biologically and pharmaceutically attractive α-methylene-γ-butyrolactone-3-spirooxindolone product was produced in 78% yield. Araki and co-workers also introduced the use of dihalocontaining allyl substrates in indium-mediated allylation. Dihalo-containing allyl substrates were found to exhibit unique characteristics in indium-mediated reaction with carbonyl compounds. For example, γ-chloroallylindium, which can be prepared by the reaction of 1,3-or 3,3-dichloropropene with indium in the presence of lithium iodide in organic solvent such as DMF, reacted with aldehydes to give chlorohydrins in good yields (Scheme 85).158,161 In contrast to these results, the indium-mediated reaction of 1,3-dibromopropene with aldehyde gave a mixture of vinyloxirane and homoallylic alcohol (Scheme 86).161,287 The former was thought to be generated from the corresponding bromohydrin involving a γ-bromoallylindium intermediate,

Scheme 80

The difluoromethylene moiety (CF2) is widely found in many fluorinated compounds that exhibit biological and pharmaceutical activities. Indium-mediated difluoroallylation of 1-bromo-1,1-difluoropropene with aldehyde serves as an efficient method for the introduction of CF2 into an organic molecule. It was found that the reactions proceeded efficiently both in DMF and in water to give the difluorinated homoallylic alcohols in good to excellent yields (Scheme 81).279,280 The reaction occurred exclusively at the α-position of the 1-bromo1,1-difluoropropene. However, ketones remained inert under the optimized conditions. Applications of this reaction as a key strategy for the synthesis of various difluorinated dihydropyr287


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Scheme 84

intermediates involved in the reaction of 3-bromo-1-iodo-1phenylpropene with aldehyde. As shown in Scheme 88, in

Scheme 85

Scheme 88

Scheme 86

addition to possible formation of routine monoallylation product C and/or D, the generation of two double-allylation products (A and B) has been observed in the use of 2 equiv of propionaldehyde (R = Et) as substrate. The formation of two possible diindium intermediates might be the key to account for the delivery of these two products (A and B) via a doubleallylation sequence (Scheme 89), whereas the use of a relatively sterically hindered aldehyde of cyclohexanecarboxaldehyde only led to two regioisomers (C and D) from monoallylation.

whereas the latter, based on a deuterium-labeling experiment, was postulated to originate from acidic quenching of an alkenyl diindium intermediate, which must have originated from an allyl gem-diindium reagent. In contrast, 1-iodo-3-bromopropene reacted selectively to give the homoallylic alcohol exclusively upon treatment of the resulting alkenyl diindium intermediate with acid (Scheme 87).287 Later in 2001, the group also proved the existence of the

Scheme 89

Scheme 87

On the other hand, Chen and Li reported that, when the above reaction using 1,3-dibromopropene was performed in water, 1,3-dibromopropene acted as a gem-allyl dianion to generate the 1,1-bis-allylated homoallylic diols as products predominately (Scheme 90).290 The mild conditions involved in the reaction allowed the utilization of substrates containing sensitive functional groups like hydroxyl, carboxyl, and cyano groups. 3-Bromo-2-chloro-1-propene can also undergo indiummediated allylation with aldehydes in water to give the 3-

diindium intermediate by subjecting the in situ-generated alkenyl diindium intermediate to palladium-catalyzed coupling with aryl, alkenyl, or allyl halides, providing a convenient onepot synthesis of linear homoallylic alcohols.288 The substrate scope was further extended to the use of allylic system of 3-bromo-1-iodo-1-phenylpropene and 2,4-diiodobut2-en-1-ol by Hirashita, Araki, and co-workers.289 One notable feature is the further verification of the existence of diindium 288


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Scheme 90

Scheme 93

Scheme 94 chlorohomoallylic alcohol products in 58−97% yields (Scheme 91).291 After subjection of the obtained homoallylic alcohols to Scheme 91

products can be further unmasked into either dihydroxyketones or cyclic ketocarbonates. A very recent finding from Xu and co-workers revealed that α-methylene-γ-butyrolactone also can be easily constructed by using 3-bromomethyl-5H-furan-2-one as allylating agent (Scheme 95).294 Its reactions with both aromatic and aliphatic

ozonolysis in methanol, the corresponding β-hydroxyesters can be afforded in 54−99% yields. The methodology provides an alternative entry to synthetically important β-hydroxyesters intermediate. 3-Bromo-2-bromo-1-propene can be used as an allylating agent as well, provided that the reaction is carried out at low temperature in aqueous DMF in order to minimize the decomposition of the allylindium reagent to allene.292 Trimethylenemethane dianion is normally prepared either through double deprotonation of isobutene or via a halolithium exchange at low temperature under anhydrous conditions with poor functional group tolerance. Li reported that the trimethylenemethane dianion can also be easily generated in situ, via the insertion of indium into 2-bromomethyl-3-bromo1-propene in water (Scheme 92).293 It reacted with aldehydes

Scheme 95

aldehydes proceeded well in water in the presence of indium to give the corresponding α-methylene-γ-butyrolactones in good to excellent yields. Especially noteworthy, in most cases, the allylated products were obtained with excellent diastereoselectivities favoring the trans diastereomers. In addition, the reaction worked better in pure water than in organic solvents. Zinc can be employed for the same purpose but with slightly declined diastereoselectivities, provided that the reactions were performed in a mixture of THF and aq. NH4Cl (2:1). Saicic et al. showed that, upon treatment with indium in aqueous THF, 2-methoxymethoxy-3-chloropropene functioned as a synthetic equivalent of an acetone enolate, undergoing sequential allylation with aldehydes and acid-promoted hydrolysis of the enol ether functionality to afford aldol-type β-hydroxyketone adducts in moderate to excellent yields (Scheme 96).295 When the same reaction was performed in anhydrous DMF employing zinc as the reaction mediator, only the methoxymethyl (MOM)-protected product was obtained, without undergoing further hydrolysis. Recently, Dhanjee and Minehan demonstrated that 2-alkoxy-substituted allyl bromides, in situ-prepared from 1,3-dibromo-2-propanol in a two-step sequence involving hydroxy protection and sodium hydride-

Scheme 92

to generate bis-allylated products in moderate yields. The reaction was less efficient when 2-chloromethyl-3-chloro-1propene was used as the allylating agent or when a ketone was introduced as the electrophile under the same conditions, giving the corresponding bis-allylated products in lower than 20% yields. Another typical example of the synthesis of β-hydroxyester was realized by using methyl (E)-4-bromo-3-methoxycrotonate as allylating reagent. Paquette and co-workers had shown that its indium-mediated reaction with aldehydes proceeded efficiently in aqueous media to give β-hydroxyesters in 58− 88% yields (Scheme 93).207 After hydrolysis of the resulting products, Knoevenagel-type adducts were eventually isolated. Recently, an interesting allylating reagent 4-(bromomethyl)1,3-dioxol-2-one, which acted as a masked hydroxyacetone, was applied in the allylation of carbonyl compounds (Scheme 94).76 The reactions proceeded rapidly at room temperature in water to provide mainly anti-α,β-dihydroxyketones. Indium was found to be superior to zinc for achieving the conversion. The

Scheme 96

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generation of a small amount of two other diastereomers (Scheme 99). The utility of this diastereoselective method was demonstrated in the synthesis of 1,4-dideoxy-1,4-L-iminoribitol.298 Additionally, the approach was applied to the functionalization of unprotected aldoses, which led, after multistep transformations, to modified aldoses with two-carbon atom elongation.299 Moreover, a strategy using this allylating agent was also utilized as a key step in the total synthesis of (+)-Asperlin.300 On the other hand, when 3-bromopropenyl methylcarbonate was used as substrate and in the presence of aldehyde and indium in DMF, the intermediate formed in situ underwent a transesterification-type intramolecular cyclization to give 4,5disubstituted 5-vinyl-1,3-dioxolan-2-ones in excellent yields (Scheme 100).301 However, when the reaction was carried

induced dehydrobromination, underwent indium-mediated allylation with various carbonyl compounds (including ketone) in DMF in the presence of tetrabutylammonium iodide (TBAI) and 4 Å molecular sieve, furnishing the corresponding homoallylic alcohols, instead of hydrolyzed products of βhydroxyketones, in acceptable yields (Scheme 97).296 Notably, Scheme 97

Scheme 100

moderate diastereoselectivities were obtained when 2-alkoxysubstituted allyl bromides containing chiral auxiliaries, such as D-glucal and (−)-menthol, were employed. The products can be easily transformed into β-hydroxy ketones and esters, as well as substituted dihydropyrans. 3-Bromo-1-acetoxy-1-propene, which can be readily synthesized by a ZnCl2-catalyzed addition of acetyl bromide to propenal, served as a synthetic equivalent of allyl anion. It underwent allylation with aldehydes in the presence of a stoichiometric amount of indium in THF to give the corresponding monoprotected 1-en-3,4-diols in yields ranging from 70% to 96% (Scheme 98).297 Generally, saturated

out in water, the aqueous media became increasingly acidic and led to decomposition of the starting material, thereby providing poor isolated yield of the target product. Commencing from (S)-Garner aldehyde, a multistep synthesis of D-ribo-Phytosphingosine employing this methodology as the key strategy was successfully executed (Scheme 101).302 Notably, the allylation step proceeded with excellent diastereoselectivity to afford the desired diastereomer in 89% yield, accompanied with the formation of two minor diastereomers in 9% yield. Araki’s group was the first to study the indium-mediated coupling of penta-2,4-dienyl bromide with carbonyl compounds. The reaction proceeded in DMF with exclusive γselectivity to give nonconjugated 1,4-diene-3-alcohol as the major product (Scheme 102).303 Ketone and sterically hindered aldehyde with a tBu substituent were inert to the reaction conditions. In addition, an extremely poor yield was observed when water was used as the sole reaction solvent. Pent-2-en-4ynyl bromide was also found to react in a similar fashion to give products with complete γ-selectivity (Scheme 103). In a later study performed by Fallis, it was reported that the reaction of 5-bromo-1,3-pentadiene with aldehydes worked equally well both in water and in DMF (Scheme104).304 In addition, sterically less congested ketones such as acetophenone and cyclohexanone also reacted to give the corresponding homoallylic alcohols in modest yields of 50−55%. When α,β-unsaturated carbonyl compounds were used, 5bromo-1,3-pentadiene added regioselectively at the carbonyl functionality in a 1,2-addition manner.303−306 Intriguingly, the resulting product, either spontaneously306 or facilitated by the addition of NaH,305 could undergo an oxy-Cope rearrangement

Scheme 98

aldehyde furnishes anti adduct, whereas α,β-unsaturated aldehyde favors the formation of syn diastereomer. In addition, indium can be made catalytic in the process by using a stoichiometric amount of manganese as metal reductant, albeit in relatively low but acceptable yield (60%). The reaction also worked well by using zinc as the reaction mediator in aqueous NH4Cl. When the protocol was extended to the use of (S)Garner aldehyde, after hydrolysis, the anti−anti diastereomer was obtained as the major product in 80% yield, along with the Scheme 99

290


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Scheme 101

to give a 1,3-dienyl ketone, an apparent direct 1,4-addition product from the initial starting materials (Scheme 105). In

some special cases, a further attack of the pentadienylindium species to the carbonyl group of the 1,3-dienyl ketone was observed.305 By using this strategy, a practical synthesis of the hydrindane ring system, an important skeleton found in many terpenoid natural products, was accomplished.306 More importantly, the dienol formed can be transformed into the versatile cross-conjugated triene, following the elimination of water (Scheme 106). This triene can undergo multiple transmissive Diels−Alder cycloaddition with appropriate dienophiles providing entry to various complex polycyclic skeletons. This strategy has been elegantly applied by the groups of Fallis and Schreiber to the construction of highly elaborated tetracyclic and even octacyclic skeletons.304,307,308 Finally, it should be mentioned that, in addition to above versatile allyl reagents, allylboronate can be used as an allyl source as well. This content will be included in the following section 2.4.4. 2.4.4. Catalytic Amount of Indium and Recovery of Indium. In comparison with other main group metals such as magnesium and zinc, indium is relatively expensive. Thus, if the allylation reaction can be achieved by using only a catalytic amount of indium, the practicality and versatility of indiummediated allylation can be markedly improved. With this idea in mind, Butsugan, Araki, and co-workers developed an economical method for the allylation of carbonyl compounds by using only 10 mol % InCl3, in the presence of 1.6 equiv of zinc or aluminum (Scheme 107).309 Satisfactory

Scheme 105

Scheme 107

Scheme 102

Scheme 103

Scheme 104

yields of the homoallylic alcohols ranging from 55% to 88% were obtained. It was proposed by the authors that the lowercost zinc or aluminum serves as an efficient reducing agent to Scheme 106

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was proposed to form through a two-step sequence involving the generation of an allylstannane by tin insertion into the allyl halide, followed by transmetalation with indium(III) trichloride. However, a stoichiometric amount of indium(III) trichloride is required in the reported method, and the topic also falls into the arena of allylstannane chemistry and, thus, will not be discussed here. Most recently, a systematic work conducted by Kobayashi and co-workers320 revealed that a catalytic amount of indium(I) salt (5 mol %) efficiently promoted the allylation of carbonyl compound, acetal, ether, and N-acylhydrazone by using allylboronate as allylating reagent (Scheme 110). With the aid

regenerate indium(0) from the reduction of InCl3. In addition, the presence of water is indispensible for the smooth reaction, suppressing the formation of undesired byproduct. Further findings from Wang and co-workers showed that, by employing an analogous Zn/InCl3 system in aqueous NH4Cl, less reactive and cheaper allyl chloride can also be used with equally good yields.310 In 2011, a similar but recyclable system by using ionic liquid [bmim]PF 6 /H 2 O (5:2) as solvent system with accelerated reaction speed was established as well.311 In addition, a catalytic amount of indium metal (10 mol %) combined with a stoichiometric amount of aluminum was also made possible for accomplishing an economical allylation reaction in DMF.312 Alternatively, Auge and co-workers demonstrated that allylation of carbonyl compound can also be achieved by using 10 mol % indium and 5 equiv of low-costing manganese as metal reductant in the presence of TMSCl, in anhydrous THF (Scheme 108).313

Scheme 110

Scheme 108

of a chiral bis(oxazoline) ligand, an asymmetric variant of the allylation was also achieved with a high level of enantio- and diastereoselectivity. In addition, a catalytic amount of indium(0) was also found to effectively promote the allylation of carbonyl compound even in water. Remarkably, an exceptionally high α-regioselectivity as well as moderate to good anti diastereoselectivity was achieved in cases where αsubstituted allylboronate was employed as substrate. In 2010, Batey and co-workers described a very mild and highly regioand diastereoselective allylation of the carbonyl group of α,βepoxy ketones by using potassium allyltrifluoroborate as allylating reagent in aqueous CH2Cl2; although a catalytic amount of indium (0.1 equiv) was also able to promote the reaction in moderate yield, the use of a stoichiometric amount of indium gave better product yield.321 Apart from the aforementioned low-cost methods employing a catalytic amount of indium(III) reagent, an alternative approach for recovering indium after reaction also represents an economical method in the use of indium reagents. As previously mentioned, indium(III) halide is generated as a byproduct after allylation. Thus, indium can be recovered by treating the resulting reaction mixture with lower-cost zinc metal to regenerate indium(0).322 Additionally, Schmid and coworkers mentioned that indium can also be recovered after the allyl addition by electrochemical reduction,323 which might be especially useful when a larger amount of indium is used. 2.4.5. α,γ-Selectivity of Allylindium Reagent. Allylation reaction of carbonyl compound using substituted allyl halide can result in the formation of either α-linear homoallylic alcohol or γ-branched homoallylic alcohol. An NMR study by Araki, Ito, and Butsugan using geranyl bromide as substrate showed that the indium insertion proceeded exclusively at the α-position of the allyl halide, with no γ-type allylindium species formed.221 On the other hand, subsequent reaction of the allylindium reagent generated with carbonyl compound proceeded exclusively at the γ-position of the allyl halide in an SN2′ manner to give γ-substituted homoallylic alcohol as the sole product, regardless of steric hindrance arising from substituents at the γ-position (Scheme 111).38 The same

Nevertheless, in view of the fact that organoaluminum314 or organomanganese315 reagents can be prepared via an indium(III) chloride-catalyzed manganese or aluminum insertion into organohalides, the possibility that the real allylmetallic reagents formed in the allylation is allylmanganese or allylaluminum rather than allylindium species cannot be ruled out. In addition, a related report regarding the preparation of allylgallium and allylaluminum sesquihalide by using a catalytic amount of indium(0) had been described as well.316 In addition to the aforementioned approaches, Hilt and Smolko discovered an electrochemical method for the allylation of carbonyl compounds by using Al as anode and Pt as cathode, in the presence of only a catalytic amount of InCl3 (5 mol %) in THF (Scheme 109).317 Of special interest is the ease with Scheme 109

which ester can be double-allylated under the electrochemical conditions, which otherwise is normally only susceptible to nucleophilic attack by conventional Li- or Mg-based allylating reagents. Close scrutiny led to the proposal that a redox process occurred at the Al anode to constantly regenerate a reactive low-valent allylindium(I) species. Application of the method to the allylation of simple imine was also realized with some success.318 Related works using a stoichiometric amount of tin were also reported for the synthesis allylindium reagents in the presence of indium(III) trichloride.213,263,264,319 The allylindium reagent 292


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holds true for the allylation of electrophiles other than carbonyl compounds such as imine.

Scheme 114

Scheme 111

believed that this was most probably due to 1,3-allylic shift of the corresponding α-allylindium species to afford predominantly the primary γ-allylindium species, hence leading to the overall α-regioselectivity of the final product. Thus, in most cases, it is extremely challenging to synthesize α-substituted linear homoallylic alcohol from structurally simple allylic halides. Fortunately, Loh and co-workers had unexpectedly found a general method to prepare α-adduct of homoallylic alcohols in the course of their studies. By using just 6 equiv of water, in the presence of either indium, zinc, or tin, the allylation reactions worked well in CH2Cl2 with a wide range of allyl halides, irrespective of their substitution pattern, to give the α-adducts in high selectivities (Scheme 115).325 A detailed mechanistic study showed that, initially, the reaction proceeded normally to give the γ-adduct. Intriguingly, after stirring the reaction mixture for a longer period of time, the initially formed γ-adduct undergoes a 2-oxonia-[3,3]-sigmatropic rearrangement with the aldehyde, either derived from the unreacted substrate or from a retro-ene bond cleavage of the γadduct, to furnish the corresponding α-adduct with high regioselectivity (up to 99:1 α/γ selectivity). While studying the allylation reaction of ethyl 4-bromo-(E)crotonate with 4-bromoacetophenone, Baba et al. also noticed a similar phenomenon as above, which involved the complete conversion of γ-adduct to α-adduct when the reaction time was extended from 0.5 to 40 h (Scheme 116).326 Finally, it is worthy of noting that the palladium-catalyzed intermolecular cross-coupling of allylindium reagent with aryl and vinyl halides also proceeds with α-selectivity.45,327 In sharp contrast, the corresponding intramolecular variant occurs with complete γ-regioselectivity (see section 2.8).328 2.4.6. Diastereoselectivity. The addition of a γ-substituted allylindium reagent to a carbonyl compound can potentially lead to a mixture of two diastereomers. The first study pertaining to the diastereoselectivity of allylation was conducted by Chan’s group (Scheme 117).324 When allyl bromide bearing a small γ-substituent (R = Me) was used, the product was furnished in a nonselective manner (50:50 anti/syn). Whereas the use of a bulkier γ-substituted allyl bromide (R = Ph or COOR) preferentially gave the products with good to excellent anti-selectivities. Acyclic or Zimmerman−Traxler329,330 transition state has been postulated to account for the varying diastereoselectivities. Interestingly, the use of both (Z)- and (E)-cinnamyl bromides resulted in the preferential formation of anti-products (Scheme 118). This behavior might be explained by a facile E/Z equilibration of the allylindium organometallic formed, as suggested by the groups of Chan and Paquette.324,331 In addition, the steric size of the aldehyde also influenced the stereochemical outcome of the allylation (Scheme 119).324 For

Subsequently, this α- versus γ-regioselectivity in water medium was studied in detail by Issac and Chan.324 In agreement with the previous observations, in most cases γregioselectivities were obtained. For example, both γ,γdimethylallyl bromide and methyl 4-bromo-(E)-crotonate reacted with benzaldehyde at their γ-positions, irrespective of the degree of substitution or the loss of conjugation of the final product (Scheme 112). Scheme 112

However, in some special cases where allyl halides bearing bulky substituents (Me3Si, Me2PhSi, or tBu) were used, α-linear homoallylic alcohols were observed as the major products, which may be attributed to significant steric effect of the substituents (Scheme 113).324 Scheme 113

As previously mentioned, another allyl halide that uniquely reacted at the α-position is 1-bromo-1,1-difluoropropene (Scheme 81). The indium-mediated coupling of 1-bromo-1,1difluoropropene with aldehydes proceeded efficiently at the αposition both in DMF and water, to give the difluorinated homoallylic alcohols in good to excellent yields.279,280 During the course of the synthesis of Antillatoxin, Loh’s group found that the lanthanum triflate helps to promote the reaction involving unreactive allylic substrates. The use of this less reactive secondary allyl bromide [(4-bromo-3methylenepentyloxy)(tert-butyl)diphenylsilane] as substrate also led to the production of the only α-adduct (Scheme 114).193 Although the real reason was unclear, the authors 293


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Scheme 115

Scheme 116

Scheme 117

Scheme 119

Scheme 118

products. Additionally, almost identical results were obtained when DMF was used in place of H2O as the reaction solvent. While exploring the total synthesis of Antillatoxin, Loh et al. investigated the allylation reactions using different allyl bromides as substrates (Scheme 120).171,193,194,197 Scheme 120

example, when cinnamyl bromide was used as the allylating reagent, the use of a sterically bulky aldehyde usually led to better anti/syn selectivity (R = Ph, iPr, or Cy). By analogy, poor anti/syn selectivity was obtained when an aldehyde with a sterically less hindered substituent was used (R = nC8H17). Similar outcomes associated with the diastereoselectivity of the allylation reaction were also observed from the investigation of Loh and co-workers.196 Significantly, it was also found that the addition of the Lewis acid, La(OTf)3, led to accelerated reaction rate and enhanced anti-diastereoselectivity in the

First, Loh and co-workers investigated the allylation reaction using β-bromocrotyl bromide as a substrate.171 Unfortunately, β-bromocrotyl bromide was not sufficiently reactive, necessitating forcing conditions in order to realize the organic transformation. Their findings revealed that the allylation proceeded sluggishly unless La(OTf)3 was added as activating 294


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Lewis acid and saturated aqueous NH4Cl was used as reaction medium. In addition, the use of ultrasonication reduced the reaction time from 36 to 16 h without compromising the product yield and diastereoselectivity. In most cases, synaddition products prevailed, with the exception of 2pyridinecarboxaldehyde, which gave 42:58 syn/anti selectivity as a result of the partial chelation control (Scheme 121).

Scheme 124

Scheme 121 also attempted by the same group. As expected, the allylation of various aldehydes, including (2E,4E)-2,4,6,6-tetramethylhepta2,4-dienal, proceeded well by employing the well-established indium-mediated allylation, in the presence of La(OTf)3 in aqueous media (Scheme 125).194 Surprisingly the syn isomers Scheme 125 However, when the method was employed in the allylation of (2E,4E)-2,4,6,6-tetramethylhepta-2,4-dienal, an advanced intermediate in the synthesis of Antillatoxin, a good yield of 70% of the desired homoallylic alcohol was obtained but with no stereoselectivity (50:50 dr, Scheme 122). Fortunately, the two diastereomers can be separated by column chromatography and used in further conversion. Scheme 122

In an alternative strategy proposed for the synthesis of Antillatoxin, Loh’s group exploited the synthesis of an advanced homoallylic alcohol from the coupling of (4-bromo-3methylenepentyloxy)(tert-butyl)diphenylsilane with aldehyde (Scheme 123).193 Again, although this less reactive secondary

were obtained as the major product regardless of the geometry of the allyl bromide used. An open-chain anti-periplanar transition state was invoked to account for the syn selectivity obtained. By employing the above well-studied allylation strategies as the key step, the total synthesis of Antillatoxin was successfully accomplished by the same group.197 Homoallylic alcohols containing a homoallylic sulfone moiety are useful building blocks in organic synthesis. While exploring the synthesis of this intermediate, Koo’s group studied the allylation of aldehyde by using haloallylic sulfone as allylating agent (Scheme 126).77,78 The indium-mediated reaction of the haloallylic sulfone and aldehyde proceeded

Scheme 123

allyl bromide was reluctant to undergo the classical indiummediated allylation, the addition of La(OTf)3 efficiently triggered the organic transformation to give the syn-isomer as the dominant adduct in modest to good yields. Interestingly, only the α-adduct was obtained in the protocol. When the actual substrate (2E,4E)-2,4,6,6-tetramethylhepta-2,4-dienal was subjected to the optimized reaction conditions, two separable diastereomers can be obtained in 75% yield with moderate selectivity (72:28 syn/anti), thus advancing the total synthesis of Antillatoxin (Scheme 124). Last but not least, the use of allylating reagent (2(bromomethyl)but-2-enyloxy)(tert-butyl)diphenylsilane in the synthesis of the key intermediate leading to Antillatoxin was

Scheme 126

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efficiently in THF/H2O with high diastereoselectivity. The diastereoselectivity was found to be mostly dependent on the R substituent irrespective of the geometry of the CC bond. When the R substituent was a methyl group, the reaction preferred a chair conformation in the indium-coordinated sixmembered cyclic transition state to give the anti-product as the major product (93:7 anti/syn). In comparison, syn-product was produced as the major isomer (93:7 syn/anti) when R was a phenyl group, suggesting the involvement of a transition state favoring the twist-boat form. The use of other metals in place of indium, such as magnesium, zinc, and tin, was not successful. An exceptionally high anti-diastereoselectivity was disclosed by Loh and Li in the indium-mediated allylation using 1,1,ltrifluoro-4-bromo-2-butene as the allylating agent (Scheme 127).79 The anti-β-trifluoromethylated homoallylic alcohols

Scheme 128

Scheme 127

over the carboxyl in the substrate. Interestingly, the use of glyoxylic acid leads to the predominant production of the corresponding syn-adduct. This conforms to the selectivity obtained from the adoption of the transition state where the allylindium reagent chelated with the ester rather than the free carboxyl. Considerable chelation effect was also observed by Bernardelli and Paquette in indium-mediated allylation of enantiopure γ-hydroxy γ-lactones.190 For example, when a lactone was vigorously stirred overnight with allyl bromide and indium powder in aqueous HCl (0.001M) containing 10% of EtOH or THF, the allylated product was afforded in 73% yield with 6.5:1 dr (Scheme 129). The addition of HCl served to Scheme 129

were predominately produced in most allylation reactions, and water was superior to DMF in inducing better diastereoselectivity. In sharp contrast, when 2-pyridinecarboxylaldehyde and glyoxylic acid were used as electrophiles, the formation of syn products was preferred. This abnormal phenomenon is largely indicative of the adoption of a Cram-chelation332 (or anti-Felkin-Anh333) transition state in the reaction, which involves coordination of the N and CO to the allylindium species. Moreover, water-soluble substrates such as formaldehyde and glyoxylic acid could be used directly. However, the use of other metals such as zinc and tin in place of indium resulted in failure of the reaction. An alternative system using Sn/InCl3 in water also provided similar high yields and excellent diastereoselectivities.319 Noteworthy is that the same principle of diastereoselectivity was also applicable to the allylation of aldehyde using tricinnamylindium which is prepared by transmetalation of cinnamyllithium with indium trichloride.334 Later, Paquette and Rothhaar performed a more detailed study of the aforementioned chelation phenomenon involving the use of 2-pyridinecarboxaldehyde and glyoxylic acid with different allyl halides (Scheme 128).335 A noteworthy example is the use of thermally stable methyl (Z)-2-(bromomethyl)-2butenoate, in such case a competitive chelation of allylindium reagent with ester functionality may be envisioned. When 2pyridinecarboxaldehyde is employed as substrate, a preferential formation of the anti-adduct is observed, reflecting a preferred chelation of the allylindium reagent to the pyridine nitrogen

accelerate the rate of unmasking free aldehyde from lactol by a ring-opening process. The high diastereoselectivity obtained can be rationalized by a chelated six-membered transition state shown in Scheme 129. That is, the coordination of a neighboring carboxylic acid group to the allylindium species locks the conformation of the bicyclic ring system, thereby causing allylation to occur preferentially on the Re face of the aldehyde. Under the same conditions, erosion of diastereoselectivity was observed in the use of another lactone, which might be explained by a competitive but detrimental coordination of the hydroxyl group to allylindium species over carbonyl group (Scheme 130). Understandably, the use of TBDPS-protected precursor not only inhibits the competitive chelation of hydroxy group over carbonyl group but also increases the shielding of the Si face of the aldehyde, therefore delivering the corresponding products with an excellent 9.6:1 dr. Remarkably, this diastereoselectivity can be further improved to 13:1 by using nBu4NBr as additive. Later, this highly diastereoselective allylation was successfully imple296


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Scheme 130

Scheme 133

Scheme 134

mented by the same group in the total synthesis of Sclerophytin A.336,337 Kumar et al. also investigated the indium-mediated allylation of several 2-oxocarboxylic acids with allyl bromides in aqueous THF. The reactions proceeded efficiently to provide the corresponding homoallylic alcohols in good yields ranging among 66−97% (Scheme 131).338,339 When cinnamyl bromide

5-Formyluracil derivatives were also proven to be suitable candidates for indium-mediated allylation in aqueous media. When cinnamyl bromide and methyl 4-bromocrotonate were used as coupling partners, an exceptionally high diastereoselectivity of >99:1 was obtained (Scheme 135).341 In sharp

Scheme 131

Scheme 135

was used as allylating agent, high syn diastereoselectivities (>99:1 syn/anti) were obtained as a result of Cram-chelation effect. The reasonable diastereoselectivities (86:14−90:10 syn/ anti) obtained with the use of ethyl 4-bromocrotonate as allylating reagent can be further improved to >99:1 syn/anti by using the corresponding sodium salts of 2-oxocarboxylic acid as electrophile and carrying out the reactions under slightly acidic condition (pH ≈ 4.7) with even shorter reaction times, suggesting a superior chelating ability of 2-oxocarboxylic acid salt over its carboxylic acid counterpart (Scheme 132). In cases

contrast, the use of 2,4-dimethoxy-5-formylpyrimidine resulted in the loss of diastereoselectivity of the corresponding products. The involvement of a chelation of allylindium reagent with the naked carbonyl group in 5-formyluracil might be responsible for the remarkable difference in the diastereoselectivity observed. As mentioned previously, the use of both (Z)- and (E)cinnamyl bromides resulted in the preferential formation of anti-products (Scheme 118) because of a facile E/Z equilibration of the allylindium organometallic formed.324,331 When a thermally stable allyl halide is used as a substrate where the allylindium reagent in situ-generated is unsusceptible to E to Z isomerization of the C−C double bond, the stereochemical outcome of the reaction is entirely controllable. One representative example is 3-bromocyclohexene in which the C−C double bond always possesses an E configuration. Thus, it acts as an efficient allylating agent for inducing highly diastereoselective allylation (Scheme 136).342 Its indiumpromoted reactions with aromatic aldehydes worked well, leading to cyclohexenyl-substituted homoallylic alcohols in excellent yields with good to excellent syn/anti diastereoselectivities (up to >99:1 dr). 2-Carboxybenzaldehyde can be used as well, and the corresponding lactone was produced as final product with 92:8 syn/anti selectivity. The use of 3-

Scheme 132

where 2-oxoglutaric acid was employed as electrophile, the allylated intermediates simultaneously underwent an intramolecular lactonization to give 5-oxotetrahydrofuran-2-carboxylic acids in excellent yields (90−95%) and exceptionally high syn diastereoselectivities (>98:2 syn/anti), which can be further transformed into 1,7-dioxa-2,6-dioxospiro[4.4]nonanes after treatment with iodine under basic conditions (Scheme 133).340 In addition, the same chelation behavior was also observed in the use of α-ketoamide (2-oxo-N-phenylpropanamide) as substrate, again giving rise to the allylated product with excellent syn selectivity (Scheme 134).339 297


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Scheme 136

Scheme 138

allylindium reagent) with various aldehydes proceeded in aqueous THF with exceptionally high syn stereoselectivity,343 which can be explained by the transition state depicted in Scheme 139. The resulting ester-containing homoallylic alcohol Scheme 139

bromocyclooctene, in most cases, delivered comparable or slightly reduced syn/anti selectivity. A Felkin−Anh sixmembered cyclic transition state was proposed to explain the syn diastereoselectivity observed. In contrast to the allylation of aldehyde, indium-induced diastereoselective allylation of ketone has not been extensively investigated. Studies from Baba’s group showed that ketone reacted with allyl halides such as cyclohexenyl halides, cinnamyl halides, and ethyl 4-bromocrotonate with high diastereoselectivity (Scheme 137).326 The choice of solvent medium was

was later proven by the same group to be a valuable intermediate for the synthesis of a wide variety of organic molecules, including α-methylene-γ-butyrolactones,343−346 γhydroxybutenolides,343 γ-alkenylbutenolides,347 γ-alkylidenebutenolides,348 benzofulvene derivatives,349 cyclobuta[α]indene derivatives,350 and tetracyclic indeno[2,1-a]Indane scaffold,351 by employing appropriate substrates in the first allylation step (Scheme 140). Normally, crotylindium sesquihalide reacts with benzaldehyde in DMF at 0 °C for 20 min to afford 1-phenyl-2methylbut-3-enol with 78:22 syn/anti ratio after acidic workup. Interestingly, a kinetic diastereoselective formation of syn

Scheme 137

Scheme 140 crucial in the reaction. In the case of cyclohexenyl bromide, the addition proceeded most efficiently in THF or DMF instead of in aqueous medium, affording the homoallylic alcohol bearing a quaternary center with syn or anti selectivity, depending on the presence or absence of chelating group. The reaction involving the utilization of cinnamyl bromide as substrate occurred more effectively in aqueous THF rather than in organic solvent, also with high diastereoselectivity (Scheme 138). In the case of the reaction of cyclohexenyl bromide with ketone bearing a chelating group (OMe), a chelated transition state was proposed by the authors, but it seems that the proposed transition state cannot explain the anti stereoselectivity obtained. Another typical example of allylating agent that reacts with carbonyl compound with syn stereoselectivity is 3-substituted (Z)-methyl 2-(bromomethyl)acrylate. As demonstrated by Kim and co-workers, indium-mediated allylation of stereochemically well-defined 3-substituted (Z)-methyl 2-(bromomethyl)acrylate (no isomerization of the C−C double bond of the formed 298


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Later, the groups of Whitesides86 and Schmid323,355 investigated the direct aqueous allylation of a range of unprotected carbohydrates containing α-hydroxyl group relative to carbonyl group, such as D-arabinose (7:1−9:1 syn/ anti), D-ribose (5:1−6:1 syn/anti), D-xylose (18:1 syn/anti), Dlyxose (16:1 syn/anti), D-glucose (5:1 syn/anti), and Derythrose (8:1 syn/anti) in the presence or absence of aq. HCl (0.1 M) or ultrasonication (note: the syn/anti selectivity shown in brackets is obtained from reactions with the parent allyl bromide). Likewise, the allylated products were furnished displaying good to excellent diastereoselectivities favoring the syn isomer. In addition, several structurally varied allyl bromides were also used to react with D-arabinose with good to excellent syn/anti selectivities, and normally, the use of sterically more hindered allyl bromide resulted in better diastereoselectivity (Scheme 143).86 These straightforward

homoallylic alcohol can be achieved as well. Findings from Lloyd-Jones’s group reveal that after forming the homoallylic indium alkoxide species it slowly decomposes in DMF if it is not quenched by an acid. In this case the anti isomer decomposes faster than the syn isomer.352 Thus, a high syn/ anti selectivity (up to 99:1) was afforded by performing the above reaction for a prolonged period of 96 h, but with a compromised product yield (19−38% overall yields, Scheme 141). Scheme 141

Scheme 143

Especially noteworthy is the compatibility of the hydroxy functionality with indium-mediated allylation in water. This has made possible the direct functionalization of unprotected carbohydrate molecules in water, which means that watersoluble carbohydrate molecules can be reacted directly without the need of onerous protection−deprotection manipulations.353 Most importantly, the neighboring hydroxyl group greatly influenced the stereo-outcome of the allylation of carbonyl compound. In 1992, during the synthesis of (+)-3-deoxy-D-glycero-Dgalacto-nonulosonic acid (KDN), Chan and Li354 reported the first direct indium-mediated allylation of unprotected carbohydrate of D-(+)-mannose in water by using 2-bromomethylacrylate as allylating agent. Interestingly, the allylated product was obtained in 6:1 dr favoring the diastereomer having a syn relationship between the newly generated hydroxy group and the C-2 hydroxyl group of mannose (Scheme 142). Although

methods served as efficient methods for the chain elongation of carbohydrate, and further elaboration of the allylated products led to the preparation of 2-deoxyaldoses, heptoses, 3-deoxy-2-uloses, and other carbohydrates. Notably, indium showed relatively better capability than tin in enhancing the diastereoselectivity of the products as well as providing cleaner products.86 Carda, Marco, and co-workers also investigated the indiummediated allylation of L-erythrulose and its derivatives in aqueous THF.356 However, the unprotected L-(−)-erythrulose underwent the allylation in a stereorandom manner, leading to only 62:38 syn/anti selectivity (Scheme 144). It seems that the

Scheme 142

Scheme 144

during that time the authors were not completely sure what kind of models they should choose to explain the good diastereoselectivity obtained in aqueous media, they did first propose that the syn selectivity can be equally explained either by a Cram-chelation model or by a Felkin−Anh model (if the neighboring hydroxy group is considered to be of medium size).72,354 At present, we generally accept that the syn selectivity observed can be elucidated by a Cram-chelation model involving the chelation of allylindium reagent with αhydroxyl group of the mannose, which is shown in Scheme 142.

competitive chelation of the primary hydroxyl group (α to the carbonyl group) with the secondary hydroxyl group led to the poor syn/anti selectivity. Thus, excellent syn/anti selectivities were afforded when the neighboring primary alcohol was preprotected by the triphenylsilyl (TPS) group (Scheme 145). By applying the same method as the key strategy in the allylation of partially protected D-xylulose, a formal synthesis of 299


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Scheme 145

Scheme 149

Scheme 150

Syributins and Secosyrins has been achieved by the same group (Scheme 146).357 Scheme 146

reacted in the same fashion to give the desired product in 83% yield with 91:9 anti/syn selectivity.358 The allylated product was subsequently used to complete the total synthesis of (+)-Boronolide by Carda and Marco. A comprehensive study of the diastereoselectivity involved in the indium-mediated allylation of α-hydroxy and β-hydroxy aldehydes in water was undertaken by Paquette and co-workers. The chemistry they developed further makes the diastereoselective allylation in water predictable and thus synthetically useful.152 A highly diastereoselective allylation of α-hydroxyaldehyde 6 favoring the formation of syn-1,2-diol was achieved in water (Scheme 151).206 This high syn-diastereoselectivity can be

In addition, it should be mentioned that the utilization of fully hydroxyl-protected carbohydrates usually resulted in the reversion of the diastereoselectivity in the allylated products favoring the anti diastereomer. For example, Schmid and coworkers showed that the use of D-glyceraldehyde led to predominant formation of syn diastereomer (1:2 anti/syn) via a chelated transition state (Scheme 147), whereas the use of fully

Scheme 151

Scheme 147

protected (R)-2,3-O-isopropylidene-D-glyceraldehyde as substrate under similar conditions resulted in a preferential formation of the anti diastereomer; the result can be rationalized by a Felkin−Anh model (Scheme 148).176 The same principle is also applicable to the allylation of protected Lerythrulose (Scheme 149).356 Another example is the use of triacetyl-protected substrate shown in Scheme 150, which Scheme 148

explained by a Cram-chelation transition state, and the results also revealed that the presence of water does not compete with the hydroxy group in coordination with the allylindium species. Again, the use of nonprotected D-arabinose 10 also led to good syn diastereoselectivity of the desired product via chelation control, whereas the use of α-hydroxy-protected substrates 7−9 and 11−13 resulted in poor syn diastereoselectivities or even 300


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154).247,360 Excellent stereochemical control was also observed in the allylation of benzoin by cinnamyl bromide under

preferential formation of the anti-diastereomers. In addition, among all the substrates 6−9 screened, α-hydroxyaldehyde 6 was found to be the most reactive and thus required a shorter reaction time, due to the chelation involved in the reaction. Remarkably, the addition of salts such as Et4NBr in the allylation of substrates 7 and 10 allowed the reactions to take place with enhanced syn-diastereoselectivities. In addition, the pH value of the reaction mixture dropped significantly as the reaction progressed, and therefore it was found that initial acidification of the reaction media also led to an increased reaction rate.206 Application of the reaction system to (E)-crotyl bromide was also investigated by the same group (Scheme 152).331 As

Scheme 154

analogous conditions, with three stereogenic centers being created with almost exclusive production of the corresponding syn,syn-diastereomer (Scheme 155).360 In comparison, the use

Scheme 152

Scheme 155

anticipated, a 5.6:1 ratio in favor of the 1,2-syn chelationcontrolled product was observed. Unexpectedly, presumably due to instability of the in situ-generated crotylindium species, an E to Z isomerization of the C−C double bond occurred prior to crotylation. Thus, the newly generated stereogenic center involving the methyl group cannot be selectively controlled, resulting in the generation of 2,3-syn and 2,3-anti products in a 1:1 ratio. A continued study undertaken by Isaac and Paquette revealed that three contiguous stereogenic centers could be set when a stereochemically well-defined methyl (Z)-2(bromomethyl)-2-butenoate was employed as the allylating reagent reacting with α-OTBS aldehyde in water. The reaction resulted in exclusive production of the 2,3-syn product.359 The predominant formation of the 1,2-anti, 2,3-syn product can be rationalized by the transition state shown in Scheme 153. The same chemical principle also holds true for the use of geometrically rigid (E)-cinnamyl bromide. Similarly, Kumar et al. observed that, when 2-hydroxyketones were exposed to indium-mediated allylation with allyl bromide in THF/H2O, syn-1,2-diols were afforded in good to excellent yields with up to >99:1 syn/anti selectivities, suggesting the existence of chelation control in the reaction (Scheme

of crotyl bromide resulted in only moderate diastereoselectivity in the third stereogenic center formed. When 2-ketoaldehydes were used as starting materials under similar conditions, highly diastereoselective bis-allylation took place, giving rise to exclusive formation of syn-1,2-bis(allyl)-1,2-diols in excellent yields (Scheme 156). Interestingly, no monoallylated product Scheme 156

was detected irrespective of the amount of allyl bromide added. By using this allylation as the key strategy, several organic compounds were synthesized and found to exhibit biological activities.361,362 When unprotected 2-hydroxycyclohexanones were used as substrates, the neighboring α-hydroxy substituent also effectively engaged in chelation-controlled allylation in water (Scheme 157).363 Here the tBu substituent served as a conformation anchor. Especially noteworthy is the cases where the hydroxy substituent is oriented in the equatorial position. Under the circumstances, a twist-boat conformation is initially adopted in order to facilitate chelation, resulting in kinetic acceleration of the reaction along with exclusive entry of the allyl group from the equatorial direction, thus leading to trans-1,2-diol entirely. 3-Hydroxycyclohexanones were not susceptible to chelation-controlled diastereoselective allylation, although excellent stereoselectivity was observed upon axial orientation of the 3-OH group, which might be explained by steric and/or electronic effects, alone or in combination. When protected 2-hydroxycyclohexanones such as 2methoxycyclohexanone and tetrahydrofuranspiro-(2-cyclohex-

Scheme 153

301


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Scheme 157

Scheme 159

anone) were utilized in coupling with allylindium reagent, chelation effect was lessened but still predominated in controlling the stereochemistry of the products (Scheme 158).364,365 Thus, the same philosophy discussed above also applies in the prediction of the stereochemical outcome of the reaction.

Scheme 160

Scheme 158

anti/syn), which is in accordance to Cram’s chelation rule. A modest level of chelation control was obtained when βmethoxybutanal (R = Me) was employed under identical conditions. Understandably, the reactions involving bulky βbenzyloxy and β-OTBS groups were incapable of chelating with the allylindium species and, thus, resulted in complete erosion of the diastereoselectivity (50:50 anti/syn). A facile entry to polypropionate moiety was accomplished by using a sequential, one-pot proline-catalyzed aldol reaction, followed by an indium-mediated allylation (Scheme 161).156 It was found that allylation of the aldol product first obtained proceeded more efficiently in water, when NaI was used as the reaction additive. Unexpectedly, syn-1,3-diol was afforded as the major product in the second-step crotylation or prenylation reaction, which is totally opposite to the anti selectivity previously observed by Paquette and Mitzel.206 The authors proposed a possible boat transition state to elucidate the syn diastereoselectivity observed. Another interesting example where chelation governed the stereo-outcome of reaction was reported by the group of Paquette as well from the use of allyl bromide carrying a hydroxy group (Scheme 162).367 Likewise, the reaction is performed in water, and an effective 1,4-asymmetric stereoinduction is realized to afford 1,4-syn-diol predominantly (up to 89:11 syn/anti). A bicyclic chelation model is hypothesized to elucidate the formation of the 1,4-syn-isomer. When the free hydroxy group is protected by a bulky TBS group, its reaction with aldehyde proceeds via an entirely different way by adopting a conventional Felkin−Anh transition state, leading to the generation of the corresponding 1,4-anti diastereomer in moderate stereoselectivity. In comparison, when 3-substituted 3-oxy-1-bromo-2-methylidenepropane with one-carbon shorter between O and Br atoms was tested, the 1,4-asymmetric stereoinduction does not

A logical extension of the work to 6-substituted 2-hydroxy-1tetralones was scrutinized by the same group as well (Scheme 159).366 Better results, in terms of both product yields and trans/cis selectivities, were attainable when the reactions were conducted in THF/H2O (1:1). On the basis of competition experiments, it was found that both trans and cis isomers were likely to form via chelated intermediates; thus, only moderate diastereoselectivities favoring the trans-diol were observed. A highly diastereoselective allylation was also achieved for the β-hydroxy aldehyde in water (Scheme 160).206 For example, the use of 3-hydroxybutanal (R = H) as substrate gave rise to chelation-controlled anti-isomer as the major product (89:11 302


Chemical Reviews

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Scheme 161

InBr3 had little effect on the product ratios. (3) Better isolated yields were obtained by carrying out the reaction in THF/H2O because of increased solubility of the substrates. The allylation reactions involving α-thia aldehydes delivered the corresponding products in diastereoselectivities ranging from 1:4 to 1.5:1 (syn/anti), indicative of the fact that SMe and SPh are poor chelating groups and thus Cram chelation is not in operation (Scheme 165).370

Scheme 162

Scheme 165

completely follow the above rules. An early study of this chemistry was performed by Mulzer and co-workers. In their case, only O-protected allyl bromides were surveyed, leading to the preferential formation of 1,4-syn-diastereomers, which can also be explained by a Felkin−Anh transition state where the bulky OR group governed the stereo-outcome of the reaction (Scheme 163).368 In addition, they noticed the positive effect of

By fine-tuning of the protecting group, a high level of asymmetric induction was realized in the allylation of N,Ndisubstituted α-aminoaldehydes.370 As shown in Scheme 166,

Scheme 163

Scheme 166

Bu4NI on the reaction rate. One year later, a detailed study conducted by Paquette and co-workers showed that, if the allyl bromide bearing a free hydroxy group was used, no pronounced diastereoselectivity was delivered (∼50:50 syn/anti), seemingly indicating that chelation control was not operative during the coupling stage (Scheme 164).369 Thus, the diastereoselectivity from using such oxygenated allyl bromide was mostly controlled by the steric size of the substituent. In addition, several characteristics of the reactions were noticed: (1) The reaction rate of oxygenated allyl bromide followed the order of OH > OMe > OTBDMS. (2) The addition of NH4Cl and Scheme 164

although the α-dibenzylamino substituent is too bulky to chelate with the allylindium complex, the α-dimethylamino group behaves totally differently to produce the syn diastereomer with excellent selectivity (>99:1 syn/anti). The size of other neighboring substituents exerts an impact on πfacial discrimination in these systems and, thus, can 303


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aminoaldehyde. Thus, the best diastereoselectivity of 97:3 in favor of the syn-isomer was achieved when tert-leucinal was utilized as reactant. The presence of water was indispensable for the reaction, and the EtOH/H2O solvent system was superior to other reaction media such as THF, CH2Cl2, and DMF. The latter usually resulted in substantive rate retardation or decreased diastereoselectivity. Upon treatment of the homoallylic alcohols obtained with acid catalyst (H2SO4 in Et2O), transesterification proceeded smoothly to produce synthetically useful α-methylene-γ-butyrolactones with yields ranging from 89% to 97%. Following the above success, Steurer and Podlech went on further to investigate whether the allylation can be achieved by using a catalytic amount of indium. After many trials, they found that the coupling of Cbz-valinal with 2-(bromomethyl)acrylate could also proceed well by using 15 mol % of InCl3 and 1.3 equiv of Al as reducing agent, providing the desired product in 79% yield with 77:23 syn/anti selectivity (Scheme 169).372 It

considerably erode the stereoselectivity. Especially noteworthy is that, in several cases where the pH is controlled at 7.0 throughout the course of the reaction, the relative proportion of syn product is greatly enhanced. Considering the fact that allylation proceeds with the buildup of acid, the basic nitrogen in the aldehyde substrate is gradually protonated by acid, which results in the repulsion of its chelation with allylindium reagent, thereby causing poor syn/anti selectivity of the reaction. By controlling the reaction under neutral conditions, such protonation can be minimized, hence improving the syn/anti selectivity as a result of the preferential adoption of a chelated transition state. As for the allylation of chiral aminoaldehyde (2S)-2(dibenzylamino)-4-methylpentanal, a moderate syn/anti selectivity of 29:71 was afforded when the reaction was performed in pure water within 48 h (Paquette’s protocol). In fact, as documented in an early work by Loh and co-workers, they found that an improved reaction rate was obtained when the same reaction was carried out in DMF/H2O (20:1) with the addition of La(OTf)3 as reaction additive (Scheme 167).192

Scheme 169

Scheme 167

is particularly noteworthy that the result is comparable to what Podlech’s group obtained from the use of a stoichiometrical amount of indium (1.1 equiv) as reaction mediator under similar conditions. The indium-mediated allylation of the aldehyde derived from in situ Dess−Martin oxidation of chiral oxazolidinone alcohol proceeded with an exceptionally high level of syn-stereoselectivity in water (Scheme 170).373 After further functionalization, the resulting homoallylic alcohol was transformed into 2,6-dideoxyamino sugar of D-vicenisamine.

Under these conditions, the reaction was completed within 0.5 h along with the production of good syn/anti selectivity of 8:92. It should be noted that, although the reaction rate was accelerated, no pronounced effects on the yield and syn/anti selectivity from the added La(OTf)3 were observed. While exploring the synthesis of α-methylene-γ-butyrolactones, Podlech’s group investigated the indium-mediated reaction of Cbz-protected α-amino aldehydes with 2(bromomethyl)acrylates in aqueous solvents (Scheme 168).371 The preferential formation of syn-configured homoallylic alcohols suggests that the allylation is governed by a chelation model. After surveying various substituted aminoaldehydes, it was found that the diastereoselectivities are essentially dependent on the bulkiness of the side-chain of the

Scheme 170

Scheme 168

In an effort to synthesize AG7088, a potential pharmaceutical lead compound for the bioavailable inhibitor of the SARS coronavirus main proteinase (SARS-CoV Mpro), an improved asymmetric induction was observed in an indium-mediated diastereoselective allylation of isoxazoloyl valinal (Scheme 171).374 As reported by Loh and co-workers, when isoxazoloyl valinal was subjected to allylation in aqueous ethanol, a key precursor for the synthesis of AG7088 was obtained with excellent syn-selectivity (98:2 syn/anti). But when Boc- or Cbzprotected valinal was used, relatively low syn/anti selectivities of 87:13 and 82:18 were afforded, respectively. This suggested that the presence of the nitrogen atom in the isoxazole moiety might be the key to account for the observed excellent selectivity, through formation of a five-membered chelation 304


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Scheme 171

Scheme 173

ring, in conjunction with the presence of the sterically bulky isopropyl group. However, when phthaloyl-protected aminoaldehydes were introduced as starting materials, the allylations with 2(bromomethyl)acrylate proceeded in a nonchelated manner, giving rise to varying levels of diastereoselectivity in the resulting homoallylic alcohols, with the anti-isomer being the major diastereomer (Scheme 172).375

glucose-derived aldehyde were observed, when Yb(OTf)3 was added as additive (Scheme 174).198 In addition, a judicious Scheme 174

Scheme 172

selection of reaction media was also essential. For instance, the use of DMF/H2O was found to be advantageous to other solvent systems such as THF/H2O or pure H2O, in terms of both product yields and stereoselectivities. The anti-diastereofacial selectivity manifested without the involvement of chelation control can be reasonably explained by invoking either the Felkin−Anh’s or Cram’s model. When highly functionalized chiral cyclopentane carboxaldehydes were exposed to indium-mediated allylation in DMF, an allylation−lactonization sequence occurred to deliver sevenmembered lactones in nearly quantitative yields as single diastereomers (Scheme 175).377 A transition state involving the chelation of allylindium reagent with the OMe and OEt groups was invoked to account for the excellent diastereoselectivity observed.

A simple preparation of chiral tertiary alcohol via an indiummediated allylation of a readily available sugar-derived ketone in water had been described by Loh and co-workers. The allylations proceeded efficiently to give the desired tertiary homoallylic alcohols in excellent yields with high diastereoselectivities (Scheme 173).376 The excellent selectivity obtained was postulated to be controlled by chelation of the in situformed allylindium intermediate with the carbonyl group and the furan oxygen instead of the OR group β to the carbonyl group. The competing chelation effect of the furan oxygen with the OR group can be proven by the fact that, when the R group was varied from TBDPS or TBS to unprotected alcohol, the diastereoselectivity decreased from 98:2 or 99:1 to 80:20. Thus, the bulky silyl groups served to impede its coordination with the allylindium species and resulted in selective chelation of this species with the furan oxygen and ketone functionality, leading to enhanced diastereoselectivity. Furthermore, water was demonstrated to be superior to other solvents such as DMF and EtOH. Moreover, in the study, the addition of Lewis acids including Yb(OTf)3 and La(OTf)3 appeared to dampen the chelation selectivity. In addition, Loh and co-workers also investigated the allylation of glucose-derived aldehyde. Again, slightly improved yields and anti diastereoselectivities in the allylation of the

Scheme 175

305


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(Figure 1); however, in most cases, either low yield or poor diastereoselectivity of the product was observed.379

Canac, Levoirier, and Lubineau developed a novel method for the synthesis of C-branched sugars or C-disaccharides by using enantiopure 4-bromo-2-enopyranoside as the allylation agent (Scheme 176).378 Its reactions with several aldehydes Scheme 176

Figure 1.

Canac, Lubineau, and co-workers also developed the synthesis of another similar allylating agent of 6-bromo-4,6dideoxy-α-D-threo-4-enopyranoside and applied it in an allylation reaction. Its reactions with aldehydes proceeded in aqueous media at pH = 7 (by using phosphate buffer) to give the desired products in moderate to good yields (Scheme 177).380 Contrary to previous cases, excellent control of the Scheme 177

were examined by using indium as mediator in aqueous media. Interestingly, the allylation proceeded exclusively at the γposition of the allyl bromide with syn stereoselectivity relative to the bromide atom. However, the stereochemistry of the newly generated hydroxyl group (from aldehyde) is governed by the steric and chelating effect of the substrates used. When benzaldehyde was used, its corresponding product A was generated as a single isomer, which can be rationalized by a sixmembered cyclic transition state I where the sterically bulky phenyl group is located in an equatorial position. No diastereoselectivity was observed in the use of butyraldehye (R = nPr) because of greatly reduced steric hindrance as compared to benzaldehyde. Intriguingly, the use of 3-O-benzyl1,2-O-isopropylidene-α-D-xylo-dialdose as substrate led to a reversed stereo-outcome, and the corresponding product B was furnished. The additional and significant chelation of the allylindium with the oxygen atom (which is close to the aldehyde) via either a six-membered ring transition state (II) or a five-membered ring transition state (III) forced the bulky sugar substituent to orient toward the pyranosidic ring in an axial position irrespective of the steric effect, thereby resulting in a reversal of stereochemistry compared to the use of benzaldehyde. However, the use of β-C-linked 2,3,4,6-tetra-Obenzyl-β-D-glucosyl aldehyde gave rise to a mixture of two diastereomers in equal amounts, possibly arising from a wellbalanced steric hindrance and chelating effect from allylindium reagent with the carbonyl substrate. Later, the same group also studied the indium-mediated allylation of aldehyde with four different isomers of the above 4-bromo-2-enopyranoside

stereochemistry at the newly generated C-1 stereogenic center was observed with all the aldehydes tested. However, the newly formed stereogenic center at C-2 cannot be fully controlled to some extent, depending on the substrate used. For example, excellent diastereoselectivities at C-2 were obtained with the use of benzaldehyde and 3-O-benzyl-1,2-O-isopropylidene-α-Dxylo-dialdose, favoring the equatorial position. The overwhelming diastereoselectivity can be explained by a transdecalin transition state where the bulky phenyl or sugar moiety adopts a more favorable equatorial orientation, rather than the adoption of a relatively less stable cis-decalin transition state. In cases where formaldehyde and β-C-linked 2,3,4,6-tetra-Obenzyl-β-D-glucosyl aldehyde were used, the formation of both equatorial and axial diastereomers were obtained, presumably because of negligible steric effect and the involvement of chelation in the reaction course, respectively, and thereby a competitive adoption of transition states between a cis- and a trans-decalin. In an effort to synthesize a precursor to anti-Bredt alkenes, Mehta and Kumaran investigated the addition of allylmetallic reagents to a norbornyl keto-acetate.381 Although good 306


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conversion was obtained by using an allylindium compound, the diastereoselectivity was extremely low (Scheme 178).

Scheme 181

Scheme 178

Khan and co-workers explored the reaction of tetrabromo norbornyl aldehyde and allyl bromide mediated by indium, during the course of the synthesis of the trans-hydrindane ring system.382 The reactions proceeded well in either aqueous media or DMSO to afford the allylated products in excellent yields with acceptable diastereoselectivities (Scheme 179).

Alcaide and co-workers reported that, when optically pure azetidine-2,3-diones were submitted to indium-promoted allylation in aqueous media, the chiral auxiliary substituted at the C-4 position efficiently controlled the attack of the allyl group from a less hindered face to give only a single isomer of the corresponding homoallylic alcohol (Scheme 182). Acidic additive such as NH4Cl, InCl3, or HfCl4 was found to greatly reduce reaction time from 18 h to 99% de) irrespective of the structure of the allyl bromide. The excellent stereoselectivity was proposed to arise from the shielding of the Si face of the electrophilic ketone functionality by a remote aromatic substituent, thus only leaving the Re face for attack. When the same reaction was carried out in DMF or MeOH, full or partial conversion of product to the corresponding lactone was observed. Allyl bromide bearing COOH functionality can be directly used without cumbersome protection−deprotection manipulation. However, when (R,R)-ketoester was exposed to the optimized conditions, no diastereoselectivity was induced (50:50 dr). In addition, changing the phenyl group to cyclohexyl group led to diminished stereoselectivity of 90:10 dr, suggesting the importance of the remote phenyl substituent in controlling the stereochemical outcome of the reaction. Implementation of the above protocol as the key strategy in the total synthesis of Dysiherbaine was met with success (Scheme 188). Only a single isomer of the desired product was obtained in 72% yield.389

Scheme 185

proposed by the authors to explain the anti diastereoselectivity observed where a chelation model seemed not operative. In addition, they found that the use of other allyl bromides such as methyl (Z)-2-(bromomethyl)-2-butenoate and O-TBS 3(bromomethyl)-2-cyclohexylbut-3-en-1-ol also led to synthetically useful level of diastereoselectivities in the final products. When two optically active 2,3-azetidinediones carrying (S)-αmethylbenzyl and (R)-(1-naphthylethyl) residues on the nitrogen center were subjected to allylation reaction under analogous conditions, the resulting diastereoselectivities were found to be directly linked to their R and S configurations, and in most cases only low to moderate diastereoselectivities were produced.386 The indium-mediated allylation of 6-oxopenicillanate and 7oxocephalosporanate in aqueous THF also proceeded efficiently to give the corresponding products as single isomers (Scheme 186).387 The chemical yield compares favorably with

Scheme 188

Scheme 186

Reetz and co-workers found that the addition of various allylmetallic reagents to 4-tert-butylcyclohexanone differentiated considerably in terms of the equatorial and axial selectivity (Scheme 189).80 The use of allylmagnesium and allyltitanium reagents preferred the formation of equatorial alcohol (axial/

the same reaction using allylmagnesium reagent. In cases where propargyl bromides were used, the propargylation reactions also occurred efficiently under similar conditions to give the corresponding products in reasonable yields. Scheme 187

308


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usually relatively low axial/equatorial selectivity was obtained in water. Interestingly, the selectivity can be modified to some extent by using aqueous facial amphiphilic carbohydrates solutions. The allylation of carbonyl compound containing a nonchelated stereogenic center at the α-position was also performed. The reaction of 2-phenylpropanal with allylindium sesquibromide proceeded to furnish the product with a diastereoselectivity of 81:19 (Scheme 192).80 Likewise, the

Scheme 189

Scheme 192

equatorial = 45:55−20:80),390 whereas the use of allylindium sesquihalide led to a reversal of diastereoselectivity, favoring the generation of the axial alcohol (axial/equatorial = 82:18). Especially noteworthy is that, by mixing tBuCH2OLi with the preformed allylindium sesquihalide, an improved diastereoselectivity (axial/equatorial = 90:10) was obtained that might be due to the formation of a modified allylindium species (indium ate complex); the thus-generated allylindium reagent bearing a bulky ligand attacked the 4-tert-butylcyclohexanone from a less hindered equatorial site, because of hindered 1,3-diaxial interaction if the attack was from the axial site, leading to preferential production of the axial alcohol. A similar trend was also seen when methyl-substituted cyclohexanone was employed: allylindium species selectively attacked the electrophiles from the equatorial site to predominantly deliver axial alcohols, and the modified allylindium ate complex exhibited better axial/equatorial stereocontrol (Schemes 190 and 191). A

utilization of the modified allylindium complex led to an improved diastereoselectivity of 89:11. Later, the method was applied by Ishigami to the synthesis of 9,12-trihydroxycalamenene diastereomers.392 In addition, Reetz and co-workers explored the reaction of allylmetallic reagents with diketones such as androstandione. Generally, allylmagnesium reagent reacted with the diketone indiscriminately, and titanium ate complex CH2CHCH2Ti(OiPr)4MgCl reacted at the 3-position in a nonstereoselective manner (53:47 dr).393 Interestingly, the mild allylindium ate complex selectively reacted at 3-position via an equatorial attack to afford the corresponding homoallylic alcohol with 86:14 axial/equatorial selectivity (Scheme 193).80

Scheme 190

Scheme 193

A later study performed by Loh and co-workers showed that the addition of a relatively bulky allylindium reagent (e.g., allylindium reagent derived from prenyl bromide and cinnamyl bromide) to chiral steroidal aldehyde afforded the product with excellent diastereoselectivity (up to 99:1 dr) in DMF, without touching the ketone functionality as well (Scheme 194).394 The excellent diastereoselectivities observed can be explained by using a Felkin−Anh transition state. Recently, a two-step sequence has been developed for the synthesis of enantiopure allylated cyclohexanol by combining an enantioselective rhodium-catalyzed conjugate addition of arylboronic acids to cyclohexenone with indium-mediated allylation in aqueous media, enabling a highly diastereoselective construction of two new stereocenters in a one-pot manipulation (Scheme 195).395 However, in cases where a third stereogenic center was created arising from the use of substituted allyl bromide, the chirality of this newly generated

Scheme 191

recent work showed that such indium-mediated allylation of substituted cyclohexanone can also be performed in water.391 However, compared to above reactions carried out in THF, 309


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Scheme 194

few of these deal with the enantioselective version of carbonyl allylation. The uncertain nature of the allylindium reagent, as well as the possible presence of more than one type of allylindium species, are two intrinsic obstacles standing in the way of surmounting this challenging task. Until now, several enantioselective protocols have been developed. However, in all the established protocols, a stoichiometric amount of chiral ligand or chiral auxiliary had to be used in order to gain reasonable enantioselectivity in the allylation product. Kang, Cho, and co-workers disclosed an indium-mediated highly diastereoselective allylation of α-ketoimides by using Oppolzer’s sultam as a chiral auxiliary.82 The reactions occurred efficiently in aqueous THF to furnish the allylated products in good yields and excellent diastereomeric excesses (Scheme 197). Crotyl bromide can be used as well with the complete

Scheme 195

Scheme 197

stereocontrol of the two stereogenic centers created in the reaction. The excellent diastereoselectivities obtained in the reactions suggested the superiority of allylindium reagent over other allylic metal reagents.397 This could be a potentially useful method for the preparation of enantiopure α-hydroxy acids upon cleavage of the Oppolzer’s sultam chiral auxiliary, which renders this protocol of demonstrable synthetic merit. The high diastereoselectivity could be rationalized by the chelated conformer where the allyl unit attacks the less hindered face. However, when the substituent of the α-ketoimide was changed from phenyl to thienyl or furyl group, the diastereoselectivity decreased, which is presumably attributed to competing but deleterious chelation of the sulfur or oxygen atom with the allylindium reagent. Further studies revealed that the diastereoselectivity can be somewhat improved by changing the solvent to aqueous ethanol. Application of a similar reaction system to the allylation of hemiacetal derived from Oppolzer’s sultam in anhydrous DMF also generated the corresponding αhydroxy camphor sultam derivatives with high diastereoselectivities (86−90% de).398 A chelated transition state was proposed by the authors to explain the excellent stereoselectivity obtained with the use of (−)-camphorsultam as chiral auxiliary. However, it seems that the proposed transition state cannot explain the stereoselectivity obtained; thus, here a slightly revised transition state was invoked by us that matches the observed stereochemistry in the work. When 8-phenylmenthyl glyoxalate was employed as substrate, its allylation reaction proceeded in water with a moderate diastereoselectivity (Scheme 198).399 The first example of an enantioselective variant of the indium-mediated allylation of aldehyde using chiral ligand was reported by Loh and co-workers. (−)-Cinchonidine and (+)-Cinchonine were successfully employed as chiral ligands in inducing enantioselectivity in organic solvents (e.g., CH2Cl2/

stereogenic center cannot be controlled. In addition, it seems that the protocol worked better with cyclohexenone because relatively poor yields and diastereoselectivities of the final products were observed in the use of five-membered and sevenmembered cyclic enone under identical conditions. Normally, enone reacted with allylindium with low diastereoselectivity until the presence of substituents close to the carbonyl group was used. For example, no diastereoselectivity was observed when using 4-tert-cyclohexenone. In sharp contrast, only one diastereomer was afforded when (R)carvone was used as substrate (Scheme 196).396 The presence Scheme 196

of the neighboring methyl and isopropenyl substituents, which blocks the equatorial position of the cyclohexenone ring, may be the reason why only attack of the allyl group from the axial position was observed. 2.4.7. Enantioselectivity. Although allylation reaction using allylindium reagent has been extensively investigated, 310


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Scheme 198

Scheme 201

hexane and THF/hexane).400,401 Moderate to good yields with up to 90% ee of the desired homoallylic alcohols were achieved (Scheme 199). However, only moderate to poor enantioseSingaram and co-workers discovered that the enantioselective indium-mediated allylation of both aldehydes and ketones can also be achieved by using commercially available (1S,2R)-(+)-2amino-1,2-diphenylethanol as chiral promoter.405−407 The reaction proceeded with both good yield (up to 99%) and enantiomeric excess (up to 93% ee) by using only 2 equiv of allyl bromide and pyridine as reaction additive (Scheme 202).

Scheme 199

Scheme 202

lectivities were furnished when α,β-unsaturated aldehyde and aliphatic aldehyde were used as substrates. The identity of the allylindium−ligand complex and reaction mechanism is unclear. A highly diastereoselective synthesis of syn-amino alcohol using the above catalytic system, commencing from a chiral αaminoaldehyde (readily accessed from D-glucono-δ-lactone), was described.402 The reaction proceeded well in the presence of (+)-Cinchonine to give an excellent syn/anti selectivity of 50:1 (Scheme 200). Without the use of (+)-Cinchonine, poor syn/anti selectivity of 2:1 was observed. Further elaboration of the syn-amino alcohol obtained led to the total synthesis of the potent glycosidase inhibitors (+)-Castanospermine and (+)-6Epicastanospermine. At the same time, Pybox was also found to be a moderately efficient chiral ligand for promoting the enantioselective indium-mediated allylation of aldehydes in aqueous medium, leading to the desired product with up to 92% ee (Scheme 201).403,404 The presence of Ce(OTf)4·xH2O was found to be essential for good yield and enantioselectivity of the reaction. It was suggested that the chiral ligand decomposed slowly under the reaction conditions, thereby limiting its broad application.

The method is tolerant toward various functional groups, such as ester, nitrile, and phenol. Crotyl and cinnamyl bromides can be used as well, delivering moderate enantioselectivities (72% and 56% ee, respectively). Mechanistic studies have suggested that, when a polar aprotic solvent is used, an allylindium(III) species is generated as the active allylating intermediate in the reaction. A recent work from Mirabdolbaghi and Dudding showed that an efficient synthesis of chiral C(3)-substituted phthalides can be achieved by using 2-formylbenzoate as substrate under the aforementioned conditions (Scheme 203).408 The reactions proceeded via an indium-mediated allylation and transesterification sequence to generate the corresponding lactones with moderate to good enantioselectivities. Density functional theory (DFT) calculations were used to rationalize the stereoselection of the reaction, and it was suggested that the enantiomeric excess of this reaction was controlled by combined effects from the steric size, chain length, and substitution of the aldehyde.

Scheme 200

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Paquette’s group developed a facile entry to various αmethylene-γ-butyrolactones through an indium-mediated allylation in water, using both alkene functionality-containing allyl bromide and aldehyde as substrate, in conjugation with a subsequent Grubbs’ catalyst-mediated ring-closing metathesis (Scheme 206).411 Various α-methylene-γ-butyrolactones fused to larger cycloalkene rings were generated with ease.

Scheme 203

Scheme 206 Aside from the mentioned methods, enantiomerically enriched homoallylic alcohols also can be produced by coupling an indium-mediated allylation with a lipase-catalyzed chemoenzymatic methodology. As reported by Chimni and coworkers, the racemic homoallylic alcohol generated from the indium-mediated allylation of heterocyclic aldehyde in aqueous media can undergo an efficient lipase-catalyzed kinetic resolution by vinyl acetate in the presence of PS-C Amino II to give the corresponding (S)-homoallylic alcohol and (R)homoallylic acetate, in most cases, with excellent enantioselectivities (Scheme 204).409 A similar strategy for the enantioselective acylation of homopropargylic alcohol was accomplishable as well.

Recently, Loh and co-workers developed a one-pot strategy for the synthesis of tetrahydropyran (THP)-ring backbone via a sequence of allylation, Prins cyclization, and InBr3/NaBH4mediated radical-type dehalogenation (Scheme 207).412 Nota-

Scheme 204

Scheme 207

bly, the indium(III) salt byproduct generated from the allylation of aldehyde can be further used in the second step of Prins cyclization, which makes the protocol economical. In addition, the methodology was applied to the synthesis of Centrolobine and Civet cat secretion in overall yields of 58% (3 steps) and 23% (5 steps), respectively (Schemes 208 and 209). Backhaus attempted the formal synthesis of Myxothiazol A by choosing indium-mediated allylation as one of the starting points (Scheme 210). However, the allylation reaction shown in Scheme 210 proceeded without stereocontrol under the conditions used.413 A short and efficient synthetic route to (±)-Methylenolactocin had been established by using indium-mediated allylation with dimethyl (Z)-2-(bromomethyl)fumarate as a key step (Scheme 211).414 The allylation worked well with hexanal under neat condition to give anti-lactone and syn-hydroxyester as major products. Both diastereomers can be effectively converted into (±)-Methylenolactocin upon further elaborations. An indium-mediated allylation of carbonyl group embedded in the benzopyranone carboxylate was utilized as the key strategy in the synthesis of methyl ether of an epimer of Heliannuol E (Scheme 212).415 Kabalka and Venkataiah have achieved the syntheses of Eupomatilones 2 by using indium-mediated allylation reactions as one of the key steps.416 The allylation of (Z)-methyl 2(bromomethyl)but-2-enoate with aldehyde proceeded with

2.4.8. Application in Natural and Unnatural Product Synthesis. The easy access to homoallylic alcohols granted by indium-mediated allylation, as well as the role of homoallylic alcohols as important building blocks, leads to the use of these compounds in the synthesis of many natural and unnatural products. This further demonstrates the utility and generality of indium-mediated allylation in organic synthesis. Araki and Butsugan developed a short formal synthesis of (±)-Bakuchiol commencing from the reaction of geranylindium sesquibromide with 2-(4-methoxyphenyl) acetaldehyde. The reaction proceeded with exclusive γ-selectivity to afford the desired product in 85% yield (Scheme 205).410 Further derivations led to the short total synthesis of (±)-Bakuchiol. Scheme 205

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Scheme 208

Scheme 209

Scheme 212

Scheme 210

Scheme 213

Scheme 211

(Scheme 214). Subsequent two-step derivations led to (+)-3deoxy-D-glycero-D-galacto-nonulosonic acid (KDN) in a concise way. Later, an improved version was developed by Fessner for the facile synthesis of KDN with 75% overall yield by Scheme 214

excellent diastereoselectivities (95:5 syn/anti) in aqueous media, with the desired syn diastereomer being the major one (Scheme 213). An ensuing lactonization catalyzed by PTSA completed the synthesis of the target molecule. The same method also led to the generation of Eupomatilones 5. As previously indicated, in 1992 Chan and Li354 reported the direct indium-mediated allylation of D-(+)-mannose in water by using 2-bromomethylacrylate as allylating agent. The allylated product was obtained in 6:1 dr favoring the desired diastereomer having a syn relationship between the newly generated hydroxyl group and the C-2 hydroxyl group of mannose, which can be rationalized by a Cram-chelation model 313


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aminic acid commencing from N-acetyl-D-(+)-mannosamin was achieved as well. An analogous diastereoselective indium-mediated allylation of either D-(+)-mannose or N-acetyl-D-(+)-mannosamin by using dimethyl (3-bromopropen-2-yl)phosphonate as allylation reagent in water was also achieved by Chan and co-workers, allowing an easy entry to phosphonic acid analogues of Nacetylneuraminic acid (Neu5Ac) and 3-deoxy-D-glycero-Dgalacto-2-nonulosonic acid (KDN), which showed moderate biological activities as sialidase inhibitors (Scheme 217).419 The same year, almost the same approach was independently developed by Whitesides and co-workers420 for the synthesis phosphonate analogues of sialic acid (Neu5Ac), commencing from the same starting materials. One thing worth noting is that, in Whiteside’s protocol, by separately forming allylindium reagent in ethanol before its addition to an aqueous solution of N-acetyl-β-D-mannosamine, pure syn allylated product was obtained in 48% yield, whereas in Chan’s one-pot protocol the product was afforded in 32% yield with 5:1 syn/anti selectivity. In 1994, Whitesides’ group described an indium-mediated allylation of acetonide-protected D-arabinose by ethyl 2(bromomethyl)acrylate in the presence of formic acid in aqueous CH3CN, leading to the corresponding product in 61% yield with 1:2 syn/anti selectivity between the newly generated hydroxyl group and the hydroxyl group at the C-2 of the Darabinose, which can be elucidated by the Felkin−Anh model (Scheme 218).186 The anti diastereomer was facilely converted into the ammonium salt of 3-deoxy-D-manno-2-octulosonic acid (KDO) with a 20% overall yields, which is complementary to the existing nonenzymatic and enzymatic methods of synthesizing KDO. In comparison, the direct allylation of unprotected Darabinose by employing ethyl 2-(bromomethyl)acrylate in water under either neutral or acidic conditions led to the predominant or exclusive formation of syn diastereomer where Cram-chelation rule governed, as revealed by Warwel and Fessner188 and Chan, Li, and co-workers.72,421 As a result, further manipulation commencing from the syn diastereomer led to the synthesis of 4-epi-KDO.188 Chappell and Halcomb applied a diastereoselective allylation in the synthesis of a six-carbon truncated sialic acid analogue (Scheme 219).422 The key step involves the indium-mediated allylation of methyl (bromomethyl)acrylate with a protected Dserine aldehyde. However, a poor diastereoselectivity in the product (58:42 syn/anti) was obtained. Fortunately, the two diastereomers could be separated and the anti-isomer could be converted into the desired syn-isomer via a Mitsunobu inversion. After further manipulations, the desired truncated sialic acid analogue was generated. Very recently, Liu and co-workers developed an efficient strategy for the total synthesis of sialic acid Neu5Ac by using a sequential rhodium-catalyzed aziridination and indium-mediated allylation of glycal.71 The allylation of glycal proceeded efficiently in the presence of indium and potassium iodide in THF, affording an eight-membered [1,2,3]-oxathiazocane-2,2dioxide, in most cases, as a single diastereomer (Scheme 220). Excellent diastereoselectivity was also observed in the use of propargylic bromide. In 2012, a short synthesis of methyl Trioxacarcinoside A by utilizing an α-chelation-controlled allylation as the key strategy was developed by Myers and co-workers.423 As exemplified in Scheme 221, after treatment of α,β-dihydroxyl ketone with indium in water, the desired allylated product was afforded with an excellent syn/anti selectivity of 15:1. Further derivations led

conducting the allylation step under acidic conditions at pH ca. 1−2, giving rise to the desired allylated product (or its corresponding lactonized product) as a single syn diastereomer.188 In 1993, Whitesides’ group189 applied the similar strategy in the allylation of unprotected N-acetyl-β-D-mannosamine in water, in the short synthesis of sialic acid. As shown in Scheme 215, upon heating a suspension of unprotected N-acetyl-β-DScheme 215

mannosamine, ethyl α-(bromomethy1)acrylate, and indium in a mixture of ethanol and 0.1 M aq. HCl, an enoate was produced (4:1 syn/anti). Ozonolysis of enoate, followed by oxidative degradation of the ozonide, and exhaustive acetylation provided protected sialic acid in 51% yield. This two-step synthesis of protected sialic acid in 46% overall yield compares favorably with previously documented routes.417 Later, the same group also extended the key allylation methodology to the synthesis of new analogues of N-acetylneuraminic acid (Neu5Ac), structurally varied at C-5, starting from N-substituted 2-amino-2deoxymannoses.418 In 1995, Chan and Lee274 reported an even shorter synthesis of (+)-KDN by directly employing α-(bromomethy1)acrylic acid as substrate (Scheme 216). The allylation proceeded with Scheme 216

acceptable diastereoselectivity (5:1 syn/anti) in water aided by indium. After lyophilization and recrystallization from ethyl acetate/methanol, pure syn diastereomer was obtained in 64% yield. Subsequent ozonolysis in methanol at −78 °C afforded the ketoacid, which spontaneously cyclized to give (+)-KDN in 95% yield. In a similar fashion, by making use of this waterbased synthetic strategy, a concise synthesis of N-acetylneur314


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Scheme 217

Scheme 218

Scheme 220

Scheme 221 to an efficient, gram-scale synthesis of methyl Trioxacarcinoside A, which is attractive for glycosidic coupling reactions. A short synthesis of the natural product (+)-Cyclophellitol, a potent β-glucosidase inhibitor, had been achieved in nine steps from D-xylose (Scheme 222).195 One of the key transformations involves a highly diastereoselective indium-mediated coupling of an aldehyde with ethyl 4-bromocrotonate. The allylation proceeded smoothly in water by employing In/La(OTf)3, affording only the desired diastereomer in 85% yield via a chelated transition state. After subsequent ring-closing olefin metathesis, ester reduction, olefin epoxidation, and deprotection, the allylic intermediate was successfully transformed into the target (+)-Cyclophellitol. An interesting one-pot method for the synthesis of the precursor of Brevicomin by coupling L-proline-catalyzed αaminoxylation of aldehyde with indium-mediated allylation was reported by Kim and co-workers (Scheme 223).424 However,

the allylation step proceeded with poor diastereoselectivity (3:2 syn/anti), although the first aminoxylation step is highly enantioselective (∼98% ee). Later, the one-pot α-aminoxylation−allylation sequence was also successfully applied by the same group to the assembly of (+)-Disparlure as well as its trans-isomer (Scheme 224).163 A similar concept by combining organocatalytic α-amination of aldehyde with allylation is described by Tae and co-workers for the synthesis of cyclic hydrazines (Scheme 225).425 The one-pot reaction involving L-proline-catalyzed α-amination of aldehydes followed by indium-mediated allylation of the crude

Scheme 219

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Scheme 222

Scheme 225

can be transformed into (1R,3R,7aS)-1-hydroxy-3-hydroxymethylpyrrolizidine in two steps (Scheme 228).427 In addition, the allylation of (S)-tetrahydrofuran aldehyde has also been examined during the attempted total synthesis of Pectenotoxin-4. The reaction proceeded smoothly in the presence of indium in aqueous DMF, generating the product in quantitative yield but with moderate diastereoselectivity (Scheme 229).102 In contrast, the same reaction performed by using allylmetallic species derived from zinc, lithium, and CrCl2 only led to poor or moderate conversion of the starting materials. During the course of the total synthesis of (−)-Englerin A, Hatakeyama and co-workers studied the metal-mediated allylation of a chiral aldehyde containing a cyclopentyl substituent. By using indium as mediator, the reaction proceeded efficiently to give the desired product in 95% yield with good diastereoselectivity (8:1 dr), whereas the utilization of zinc or CrCl2 as reaction promoter resulted in relatively low yield and a significant erosion of product diastereoselectivity (Scheme 230).100 The good diastereoselectivity obtained with the use of indium can be explained by a nonchelated Felkin− Anh model. In addition to the examples shown above, the application of indium-mediated allylation in the total synthesis of several other natural and unnatural products, such as Iriomoteolide1a,428 (−)-Laulimalide analogues,429 Spongistatin 1,430 multisubstituted cyclopentane,431 and others,432 have also been reported. 2.4.9. Intramolecular Addition. An indium-mediated intramolecular allylation of a substrate incorporating both ketone and allyl halide moieties was established in water by Li and co-workers for the construction of five-membered cyclopentanol (Scheme 231).433 Particularly interesting is the formation of bicyclo[n.4.0]octane derivatives (n = 1, 2). Interestingly, as demonstrated by Li and co-workers, in cases where a four-434 or three-membered435 ring was first formed during the intramolecular allylation of cyclic ketone, the intermediates readily underwent rearrangement to produce two- and one-carbon ring-expansion products, respectively. Relief of ring strain of the newly generated bicyclic system was believed to be the driving force. For example, when substrate

Scheme 223

α-hydrazino aldehydes yielded 1,2-amino alcohols with high enantio- and diastereoselectivities. The excellent anti selectivity achieved in the allylation can be explained by a Felkin−Ahn transition state rather than the Cram-chelation model due to the overwhelming steric effect arising from the bulkiness of the CbzNNHCbz group. More recently, the same group also described an analogous strategy for the preparation of anti-1,2diol, as well as subsequent asymmetric total synthesis of (−)-6acetoxy-5-hexadecanolide, by using a one-pot (−)-(S)-α,αdiphenylpyrrolidine-2-methanol trimethylsilyl ether-catalyzed asymmetric α-benzoyloxylation of dodecanal with benzoyl peroxide followed by an indium-mediated allylation. A reasonable diastereoselectivity and excellent enantioselectivity of anti-isomer were also produced under well-selected conditions (Scheme 226).426 A stereoselective formal total synthesis of (−)-Swainsonine featuring an indium-mediated allylation of (S)-Garner aldehyde was accomplished by Murthy and Nageswar (Scheme 227).209 The allylation step proceeded well to furnish the allylated product in good yield (85%) with acceptable diastereoselectivity in favor of the anti diastereomer (3:1 anti/syn). When N-Cbz-L-prolinal was used as substrate, its indiummediated allylation proceeded with a high level of stereocontrol to give the corresponding product with both good yield (78%) and good diastereoselectivity (>95:5 dr). The allylated products Scheme 224

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Scheme 226

Scheme 227

Scheme 231

Scheme 228

Scheme 232 Scheme 229

functionalities was mixed with indium in water with stirring, an intramolecular cyclization occurred followed by lactonization to give exclusively the cis-fused α-methylene-γ-butyrolactone (Scheme 233). The formation of cis-fused lactone can be rationalized by a preferred adoption of chair−chair conformation rather than an alternative chair−boat option.

Scheme 230

Scheme 233

14 was treated with indium in water, an intramolecular allylation occurred to generate intermediate 15, which subsequently underwent ring-opening through a retro-aldol reaction, leading to the formation of carbocycle 16 with differing ring size (Scheme 232). After subjecting 16 to 1,8diazabicyclo[5.4.0]undec-7-ene (DBU)-mediated isomerization, the more stable conjugated product 17 was eventually formed. The use of water as solvent was found to be essential for success of the ring-expansion reaction. Another interesting intramolecular version of indiumpromoted allylation was reported by Bryan and Chan.436 When a substrate containing both allyl bromide and aldehyde

The utility of indium-mediated intramolecular allylation was also demonstrated by the synthesis of chromane, which is commonly seen in many natural products. Good reaction efficiency was achieved when the reaction was conducted in aqueous media with the addition of 2 equiv of HCl (Scheme 234).191 An alternative system for the synthesis of chromane by employing In, InCl3, and a catalytic amount of Pd(PPh3)4 in THF/H2O also entailed the use of allyl acetate as allyl source, in which the organoindium reagent was believed to evolve from 317


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Scheme 234

Scheme 236

the reaction of in situ-generated π-allylpalladium(II) complex with In/InCl3.437 The study of an intramolecular indium-promoted cyclization of 4′-substituted (Z)- and (E)-7-bromo-5-heptenophenones in aqueous THF was undertaken by Paquette and Mendez-Andio (Scheme 235).438 In every instance, ring-closure occurred to Scheme 235

containing homoallylic amines as the main products (Scheme 237). Scheme 237

Vilaivan and co-workers found that, in addition to aprotic solvent such as THF and DMF, alcoholic solvent is also a solvent of choice for allylation of imines (Scheme 238).64 The deliver syn-2-vinylcyclopentanol exclusively, irrespective of the double-bond geometry in the starting material. The excellent stereo-outcome can be accounted for by adopting specific transition states depending on the substrate used. Competitive study showed that intramolecular allylation proceeded preferentially and exclusively even in the coexistence of benzaldehyde (1 equiv) in the reaction.

Scheme 238

2.5. Addition to Imine

imines underwent allylation in methanol to furnish homoallylic amines in yields varying in the range 20−79%. Imines derived from enolizable aliphatic aldehydes also worked, albeit in moderate to poor yields. In contrast, when indium was replaced by tin or zinc, no desired allylation product was obtained. Later, the substrate scope was somewhat extended by Méndez and Kouznetsov to the use of imines derived from furyl and thienyl aldehydes.443 The feasibility of carrying out indium-mediated allylation of imine in ionic liquid, [bpy]BF4, was established by Chan and co-workers (Scheme 239).217 Through fine-tuning of the ionic liquid solvent system, they found that addition of a specified amount of [bpy]Br (0.1−0.2 g on a 0.5 mmol scale of imine) was critical for inhibiting the formation of an undesired bisallylated byproduct. Under optimized reaction conditions,

2.5.1. Addition to Imine and Related Derivative. Homoallylic amines are important synthetic intermediates for the synthesis of many nitrogen-containing natural products439 and biologically active compounds.440 Among the various methods developed, metal-mediated allylation of imines serves as a straightforward method for the synthesis of various homoallylic amines.441 The first indium-mediated allylation of imine was investigated by Mosset’s group. The reactions were carried out in THF, and good yields of homoallylic amines were obtained when imines derived from aromatic aldehydes and anilines were used (Scheme 236).83 However, poor to moderate conversions were observed when imines containing aliphatic substituents (especially sterically hindered ones) were employed. One advantage of the method is that the α,β-unsaturated iminium system only reacted in a 1,2-addition manner, while the potentially competitive 1,4-addition, which often occurs with the use of allyllithium reagent, was not detected. Moderate diastereoselectivity of 4:1 was obtained when imine derived from (S)-phenylethylamine was used. The same reaction operated in DMF was exploited by Butsugan’s group, which furnished the expected homoallylic amines in satisfactory yields.442 Interestingly, when imines derived from aliphatic amines such as methylamine and benzylamine were used as starting material, further attack of the resultant amino anion on DMF ensued to give formyl-

Scheme 239

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Enamine can also be considered as an imine equivalent under appropriate conditions. Mosset and co-workers discovered that, when enamine was exposed to allylindium sesquihalide in THF, the equilibrium slowly shifted to the side of the imine (presumably promoted by the slight acidity from the glassware or the Lewis acidity of the generated allylindium sesquihalide), and thus allylation occurred to give tertiary homoallylic amines as products.183 Later, they found that the addition of 1 equiv of acetic acid (or trifluoroacetic acid) greatly shifted the reaction equilibrium from enamide to iminium salt and thus led to an accelerated speed of the subsequent indium-mediated allyl addition (usually reaction time was reduced from several or many hours to within 1 h) (Scheme 243).113 In addition, only 2/3 equiv of indium was required. Notably, among many metals tested, indium emerged as the best mediator for the transformation.

various imines were selectively monoallylated in 62−99% yields. The allylation of imine or sulfonimine can also be realized by using poly(propylene) glycol (PPG, molecular weight (MW) ca. 1000) as a reaction solvent, in conjunction with activation by ultrasonication.174 High yields of the desired products, coupled with the recyclability of the PPG, render this protocol synthetically attractive. α-Methylene-γ-butyrolactams, as biologically active compounds, can be constructed via an indium-induced coupling of 2-(bromomethyl)acrylic acid with various imines, followed by dicyclohexylcarbodiimide (DCC)-mediated lactamization (Scheme 240).444 However, only poor to moderate yields of the final products were obtained, especially for alkyl-substituted imine. Scheme 240

Scheme 243

As mentioned previously,287,288 1-iodo-3-bromopropene reacts with indium to generate an allyl diindium intermediate. Analogous to its reaction with aldehyde, it can also react with imine to generate an alkenyl diindium intermediate. Subsequent cross-coupling of the resulting intermediate with aryl, alkenyl, or allyl halides under palladium catalysis afforded linear homoallylic amines in moderate yields, in a one-pot sequence (Scheme 244).447

Enol ethers can be used as an aldehyde equivalent. When an enol ether (e.g., ethyl vinyl ether) was mixed with aromatic amine, allyl bromide, and indium in THF, the in situ generation of imine followed by allylation afforded diverse homoallylic amines in a one-pot protocol (Scheme 241).445 However, Scheme 241

Scheme 244

under the same conditions, aliphatic amine failed to undergo the one-pot reaction; instead, it directly coupled with allyl bromide via a nucleophilic substitution to afford the corresponding allyl-substituted amine, rather than the desired homoallylic amine. Aminoalkoxy titanium complex, an intermediate generated from the condensation of aldehyde, dibenzylamine, or diallylamine in the presence of titanium(IV) isopropoxide, also acts as an imine equivalent and undergoes nucleophilic addition with allylmetallic reagents (Scheme 242).446 The reaction can be

In contrast to indium-mediated allylation of carbonyl compound in aqueous media, the allylation of imine in water proved to be more difficult. This might be attributed to the following reasons: (1) Intrinsically, an imine is less electrophilic than a carbonyl compound. (2) Some imines are unstable and tend to hydrolyze in water, particularly aliphatic ones. (3) The formation of allylic alcohol competes with the generation of homoallylic amine. (4) In aqueous media, an imine is prone to undergo homocoupling rather than the desired allylation to give 1,2-diamine, in the presence of indium (Scheme 245).448 As a result, until now few indium-promoted allylations of simple imine in aqueous medium have been realized. The only one known example is the use of imines generated in situ from 2-pyridinecarboxaldehyde or 2-quinolinecarboxaldehyde with aryl amines (Scheme 246).449 The indium-mediated allylation

Scheme 242

Scheme 245 performed in a two-step, one-pot manner, mediated by either indium or zinc, furnishing homoallylic amines in 58−83% yields. It is worthy to note that moderate to good yields were also achieved when aliphatic aldehydes were used in the protocol. 319


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Scheme 246

Scheme 248

with these two substrates occurred well in aqueous media to provide the corresponding homoallylic amines in 75−89% yields. However, the substrate scope is severely limited because other aldehydes cannot be used, a reflection of the important role of the nitrogen atom attached to the α-carbon of the aldehyde, which might enhance the substrate reactivity through a chelation with allylindium species. Intriguingly, the utilization of crotyl and cinnamyl bromides furnished the products with good to excellent diastereoselectivities (up to 98:2 dr). On the other hand, sulfonimine is a good alternative to simple imine because of its inherent advantages including high electrophilicity, stability toward water, and ease of cleavage of the sulfonyl group. Chan and Lu have shown that allylation of sulfonimine occurs efficiently in THF/H2O to give homoallylic sulfonamide in moderate to good yields (Scheme 247).450,451

Scheme 249

obtained racemic homoallylic amine by lipase PS-D in the presence of different acyl donors to provide the enantiomerically enriched one has also been executed.454 Water-tolerant tosylhydrazone and nitrone also proved to be reactive electrophiles toward indium-promoted allylation reaction in aqueous media (Scheme 250). 455 Various

Scheme 247 Scheme 250

Aliphatic sulfonimines exhibited relatively poor reactivity when compared to their aromatic counterparts. When crotyl bromide was used as an allylation reagent, depending on the solvent system used, the sole formation of γ-adduct with varying modest diastereoselectivity was observed. Interestingly, the use of cinnamyl bromide led to >99:1 dr favoring the syn isomer. Meanwhile, zinc also can be used as a metallic mediator to give better performance than indium, when saturated aqueous NH4Cl was used as the reaction medium. The same group also studied the diastereoselectivity involved in the crotylation of sulfonimines bearing a proximal chelating group in THF/H2O (1:1). In most cases, especially when the reactions were performed in an equivolume mixture of THF and water instead of in pure water, the preferential formation of syn crotylation products were observed with good diastereoselectivities, seemingly establishing the possible involvement of chelation effects (Scheme 248).452 Leino and co-workers extended the allylation of imine to N,N-(dimethylsulfamoyl)-protected imine. Moderate to good yields of N-homoallylic sulfamides were obtained by performing the reaction in THF mediated by indium (Scheme 249).453,454 Zinc can be used as well, although indium exhibited better efficiency for the reaction. In addition, THF was superior to aqueous THF as reaction solvent because the use of the latter solvent system also led to the hydrolysis of the reactant. The N,N-dimethylsulfamoyl group in the product can be readily removed in refluxing 1,3-diaminopropane to provide the homoallylic amine. An enzymatic kinetic resolution of the

homoallylic tosylhydrazides and hydroxylamines were furnished in good to excellent yields under these conditions. Recently, an indium-mediated allylation of N-benzohydrazones in DMF by using 3-bromo-3,3-difluoropropene as allylating agent has also been described.456 The 3-substituted 3-amino-2-oxindole skeleton, featured in a range of natural products and biologically active compounds, can be easily prepared via an indium-induced allylation of imino-isatins (Scheme 251).202 The Barbier-type reaction worked efficiently in a mixture of THF and saturated NH4Cl solution, in the presence of Lewis acid additive such as InCl3 or AgOAc. Scheme 251

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Trifluoromethyl-containing α-aminoalkylphosphonate, a potentially biologically active compound, can be effectively constructed through the indium-promoted allylation of αiminotrifluoroethylphosphonates in THF and in the presence of acetic acid (Scheme 252).178 The addition of acetic acid as an additive exerts a positive effect on both product yield and reaction rate.

Glyoxylate imines can be allylated as well. Both indium and zinc can efficiently mediate the reaction in solvents such as THF, DMF, or a mixture of THF/aq. NH4Cl (1:1) (Scheme 255).180 A one-pot, three-component reaction was also Scheme 255

Scheme 252

achievable for the synthesis of the same product through in situ generation of the glyoxylate imine, starting from the corresponding aldehyde and amine. A very recent study conducted by Babu and co-workers showed that excellent diastereocontrol was achievable when γ-substituted allyl bromides were used (98:2 dr, Scheme 256).99 For example,

In comparison, most oxime ethers are reluctant to undergo indium-mediated allylation. Only oxime ethers derived from 2pyridinecarboxaldehyde and glyoxylic acid are reactive enough to be allylated in water, presumably because of the enhanced reactivity due to the existence of an additional chelation site.457 When (E)-cinnamyl bromide or (E)-bromocrotonate was used, excellent diastereoselectivity in favor of the syn-isomer was isolated (>99:1 dr), which can be rationalized by the two transition states shown in Scheme 253.

Scheme 256

Scheme 253

the use of (E)-crotyl and (E)-cinnamyl bromides led to the preferential formation of the anti-adducts, while the use of cyclohexenyl bromide (Z configuration) resulted in the preferential formation of the corresponding syn-adducts. In addition, indium was found to be superior to other metals, such as zinc and tin, for effecting these transformations. The excellent diastereoselectivities obtained can be explained by a chelated transition state shown in Scheme 256. In comparison, α-hydrazono ester only reacted with moderate diastereoselectivity. The usefulness of this highly diastereoselective protocol has been illustrated by the synthesis of 2,3-disubstituted Naryltetrahydropyridine, 2,3-disubstituted N-aryl piperidine, and N-aryl Baikiain derivatives, bearing two contiguous diastereogenic centers. Intramolecular cyclization of substrate embedded with both imine and allyl bromide moieties can take place in the presence of indium and acetic acid in either THF or DMF with moderate success.185 Remarkably, only cis-chromane was obtained, which can be explained by a chairlike transition state illustrated in Scheme 257. However, the use of aqueous THF as reaction solvent only has a detrimental effect on product yield. 2.5.2. Diastereoselectivity. Prior to 1997, only sporadic examples concerning the indium-mediated diastereoselective allylation of imine bearing chiral auxiliary (such as imines derived from (S)-phenylethylamine) were reported.83,458 However, the moderate diastereoselectivities (50−60% diaster-

The more electrophilic glyoxylate oxime ether or ester is also sufficiently reactive to undergo allylation reaction. When these substrates were exposed to indium-mediated allylation in the presence of trifluoroacetic acid (TFA), homoallylic amino compounds could be isolated in fair to excellent yields (Scheme 254).179 In cases where acetic anhydride was used in place of TFA, the corresponding N-acyl amino compounds were formed in 47−84% yields. Scheme 254

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Scheme 257

Scheme 259

eomeric excess (de)) of the generated products make the methods less attractive in organic synthesis. In 1997, Loh and co-workers described the first systematic study regarding asymmetric allylation of imine utilizing chiral auxiliary with a synthetically useful level of diastereocontrol.151 In their studies, it was found that a heightened level of diastereoselectivities was achieved when imines derived from Lvaline methyl ester were used as substrates (Scheme 258).

was extended by the same group to the synthesis of sixmembered cyclic guanidines and thiourea.461 Vilaivan and co-workers reported that, by applying their previously developed reaction system in methanol64 to imine derived from chiral (R)-phenylglycinol, various homoallylic amines were afforded with good to excellent diastereoselectivities (81:19−98:2 dr, Scheme 260).462 Enolizable imines

Scheme 258

Scheme 260

derived from aliphatic aldehydes also exhibited high performance, in terms of reaction yields and diastereoselectivities. The chiral phenylglycinol auxiliary can be readily removed without racemization to provide easy entry to optically active homoallylic amine. The high diastereoselectivity could be rationalized by the formation of a rigid five-membered ring transition state involving chelation of the allylindium with the nitrogen and oxygen atoms of the substrate. Owing to the blockage of the Si face by the phenyl substituent, the addition of the allyl group to the iminium compound can selectively take place from the opposite side of the phenyl group (Re face). Imines derived from uracil were also proven to be good candidates in undergoing indium-mediated allylation by carrying out the reactions in THF/toluene. A highly diastereoselective allylation was achieved in the use of 5iminyluracil derivatives bearing a chiral auxiliary of amino alcohol, leading to the desired products with up to >98:2 dr (Scheme 261).341 No reaction took place either in THF or in

These imines coupled smoothly with allyl bromide in a one-pot manner in DMF to offer various homoallylic amines in acceptable yields with up to 99:1 dr. Aliphatic imine also proved to be a suitable candidate for the reaction. In addition, glyoxylic acid monohydrate can be directly allylated without the need for prior protection. However, the addition of another Lewis acid as reaction promoter seemingly had a negative effect on the reaction outcome, in terms of both product yield and stereoselectivity. The chelation of allylindium species with the nitrogen and the carbonyl group of the ester, combined with facial shielding conferred by the bulky isopropyl group of the valine chiral auxiliary, forces the allyl addition to take place almost exclusively at the Si face, thus predominately providing (S,S)-diastereomers. A similar strategy using zinc as mediator was applied by the same group to the total synthesis of (−)-Epibatidine.459 In 2001, a similar system using the enantiopure α-amino alcohol of (S)-valinol as chiral auxiliary was developed by Yanada, Kaieda, and Takemoto (Scheme 259). Of the various allyl substrates tested, most of the reactions proceeded with exceptionally high asymmetric induction (>99% de) in aprotic solvent (DMF) by using indium as mediator. An alternative method using In, I2, and a catalytic amount of Pd(PPh3)4 in DMF also entailed the use of allyl acetate and allyl phenyl ether as allyl source, in which the allylindium reagent was believed to evolve from the reaction of in situ-generated π-allylpalladium(II) complex with In/I2 (or InI).460 Later, the former approach

Scheme 261

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diastereoselectivities (92:8−99:1 dr).467 The chiral auxiliary can be removed with ease, which allows for the convenient synthesis of enantiomerically enriched homoallylic amines. This well-established methodology was later applied by the groups of Foubelo, Yus, and Das to the synthesis of pyrrolidin-3-ol,468,469 2-(hydroxymethyl)azetidines, 469 α-methylene-γ-butyrolactam470,471 (Scheme 263), naturally occurring 2,6-cis-disubstituted piperidines [e.g., (+)-Isosolenopsin and (R)-Coniine],466,472,473 (S)-Coniceine (Scheme 264),473 dendrobate

aqueous THF. The method was later applied by the same group to the synthesis of several analogous compounds bearing indole, pyridine, and pyrimidines moieties, and some of them were found to show appreciable anticancer activities.463 A highly diastereoselective allylation of imino ester (derived from trifluoropyruvate) bearing a chiral auxiliary of (R)phenylglycinol methyl ether has also been achieved by using indium as mediator (Scheme 262).464 As reported by Zhang Scheme 262

Scheme 264

alkaloid (+)-241D,474 and Aphanorphine.475 It is noteworthy that a recent advancement made by Sirvent, Foubelo, and Yus showed that the method can be further extended to the use of N-tert-butanesulfinyl ketimines as substrates with comparable success in diastereocontrol.476 Very recently, Taddei and co-workers found that (1R,2S)-1amino-2-indanol also functioned as an efficient chiral auxiliary, in inducing high stereocontrol in the allylation of in situgenerated imine. The corresponding homoallylic amines were obtained with up to >99:1 dr when the allylation was carried out in the presence of indium in methanol (Scheme 265).477

and co-workers, up to >20:1 dr of the final product was obtained. γ-Substituted allyl bromide can be used as well with the control of the diastereoselectivities of the two newly generated stereogenic centers. The high diastereoselectivity may be explained by postulating a highly restricted chair transition state where indium coordinates with CN, MeO, and carbonyl group, and thus allyl group attacks the sterically less hindered Si face of imino ester. The formed product can be further applied to the synthesis of 2-allyl-2-(trifluoromethyl)aziridine. Foubelo and Yus found that imines bearing chiral sulfinyl auxiliary also underwent allylation reaction with high diastereoselectivities. By reacting preformed chiral N-tertbutylsulfinyl imines (derived from aldehydes) with allyl bromides in the presence of indium powder in THF at 60 °C, the corresponding N-tert-butylsulfinyl amines were obtained in good yields and diastereoselectivities, upon hydrolysis with water.465 The high diastereoselectivity can be explained by the transition state shown in Scheme 263. A one-

Scheme 265

Scheme 263

After further elaborations featuring a Rh(I)-catalyzed hydroformylative cyclohydrocarbonylation, a variety of enantiomerically pure 2-, 2,3-, 2,6-, and 2,3,6-substituted piperidines and 1,4-substituted indolizine can be readily accessed. Indium-mediated allylation of (R)-N-benzyl-2,3-O-isopropylideneglyceraldimine with 4-bromo-1,1,1-trifluoro-2-butene gave the desired homoallylic amine in 61% yield with excellent diastereoselectivity (Scheme 266).478 Unexpectedly, contrary to the allylation of the corresponding aldehyde, which usually led to the preferential generation of the anti diastereomer because of steric interaction, the reaction involving the imine proceeded via a chelated transition state to give the syn diastereomer as the only product (>99:1 syn/anti). After further manipulations, the methodology can be applied to the stereoselective synthesis of (2R,3S)- and (2S,3R)-4,4,4-trifluoroisoleucines and (2R,3S)4,4,4-trifluorovaline.

pot method for the synthesis of chiral homoallylic amine by using an in situ-generated imine, which can be readily prepared by treating aldehyde and (S)-N-tert-butanesulfinamide with water-scavenger Ti(OEt)4, was also developed.466 In 2008, efforts from Lin and co-workers revealed that, simply by adding NaBr as additive, the above reactions can be performed even in water at room temperature with improved yields and 323


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substituted allyl halides such as crotyl and cinnamyl bromide were reluctant to participate in the reaction even under the optimized conditions. An intramolecular variant of the allylation using allyl bromide tethered chiral hydrazone as substrate was also successfully accomplished by Cook’s group (Scheme 269).181 The reaction

Scheme 266

Scheme 269

Oppolzer’s sultam, when incorporated into imine, greatly enhanced the diastereoselectivity of its allylation reaction. The resulting homoallylic amine was obtained with 90% de (Scheme 267).398 A transition state formed by chelation of an oxygen Scheme 267 occurred with the assistance of added carboxylic acid to give the product bearing a chromane framework, with complete cisstereocontrol. The addition of carboxylic acid such as trifluoroacetic acid or Boc-Gly-OH was crucial in initiating and driving the reaction to completion. Other acids such as In(OTf)3, HCl, or MsOH proved to be futile for the reaction. The acid was postulated to activate the reaction through hydrogen bonding to the oxazolidinone carbonyl, as well as to simultaneously enhance the nucleophilicity of the allylindium by coordination of the acid carbonyl to the indium center. During the course of synthesizing Calystegine alkaloid, Skaanderup and Madsen met with difficulty in achieving a highly diastereoselective allylation of an in situ-generated imine derived from a fully protected enantiopure aldehyde in the presence of zinc (R/S = 2:1). Simply by changing the metal from zinc to magnesium or indium, an improved diastereoselectivity was observed (Scheme 270).65 It was particularly

atom of the sulfonyl group and the nitrogen of imine with the allylindium could help to account for the high diastereoselectivity obtained. Later, a similar finding was also independently reported by Naito’s group.479 Cook and co-workers had discovered that indium-mediated allylation of valinol-based chiral hydrazones worked well with modest to excellent diastereoselectivities and almost quantitative yields (Scheme 268). 205 In cases where modest

Scheme 270

Scheme 268

noteworthy that only one diastereomer was isolated when indium was used as mediator. The outcome may be explained by the strong chelation of in situ-generated allylmagnesium and allylindium reagents with the α-benzyloxy group. Very recently, a direct indium-mediated allylation of imine derived from unprotected D-pentoses and aliphatic/benzylic amines has been accomplished by performing the reaction in MeOH (Scheme 271).98 In most cases, excellent diastereoselectivities were obtained, with the syn diastereomer being predominant, which can be explained by a chelation model. In contrast, the use of zinc and tin as reaction promoters proved

diastereoselectivities were observed, the utilization of 1.3 equiv of In(OTf)3 significantly improved both the diastereoselectivities and the reaction rates. It was hypothesized that the Lewis acid coordinated with the hydrazone in a chelating fashion to activate the substrate, as well as restrict the conformational mobility, thus allowing for enhanced reactivity and selectivity. Gratifyingly, reaction with hydrazones derived from aliphatic aldehydes also proceeded with high efficiency. However, the substrate scope is limited because other 324


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allylic amines in moderate to good yields with up to 92% ee (Scheme 274).481 Improved enantioselectivities were attained

Scheme 271

Scheme 274

to be unsuccessful. In addition, the use of (R)- and (S)-αmethylbenzylamine as substrates led to both decreased yields and decreased diastereomeric excesses. Interestingly, in the case where allyl amine was employed, the obtained allylated product can be transformed into optically active 1,2,3,6-tetrahydropyridine after ring-closing metathesis. In addition to D-pentoses, other unprotected carbohydrates, including D-arabinose, Dlyxose, and D-ribose, have also been attempted, affording the desired homoallylic amines in 62−88% yields with good to excellent diastereomeric excesses (up to >95 de). A variant of the indium-mediated allylation of imine using 4acetoxy-2-azetidinone as an imine equivalent was described. The reaction proceeded smoothly to deliver 4-allyl-substituted azetidinones in 80−92% yields, with retention of the chirality initially installed in the substrate (Scheme 272).157 DMF is the solvent of choice, and KI as additive is critical for the efficient progress of the transformation.

when 100 mol % of the ligand was employed, whereas essentially enantiopure products were obtained upon further recrystallization. The addition of a molecular sieve was found to be helpful because water appeared to have a detrimental impact on the enantioselectivity of the reaction. The use of other chiral ligands such as bisoxazoline, chiral amino alcohols, and chiral diamine derivatives were not very successful. It was subsequently found that the reaction could be made considerably more efficient by using sulfone BINOL as a chiral ligand (Scheme 275).482 In the presence of 10 mol % chiral Scheme 275

Scheme 272

2.5.3. Enantioselectivity. In contrast to the asymmetric allylation of electrophiles incorporated with chiral auxiliary, the use of only a catalytic amount of chiral catalyst to induce chirality into the product is far more attractive and synthetically useful. Kim and co-workers attempted the indium-mediated allylation of imine by using (+)-Cinchonine as a chiral ligand (Scheme 273).480 However, only poor to moderate enantioselectivities of 20−44% ee of the homoallylic amines were yielded. Significant advancement was achieved by Cook’s group using 2,2′-binaphthol (BINOL) as a ligand. With only 10 mol % (R)3,3′-bistrifluoromethyl BINOL, the indium-mediated allylation of hydrazone proceeded smoothly, providing various homo-

ligand, Cook, Lloyd-Jones, and co-workers observed an improvement of both chemical yield and enantiomeric excess. In addition, the substrate scope was further expanded by using allyl bromide and aliphatic hydrazone as substrates with good selectivities. Later, Tan and Jacobsen demonstrated that a chiral catalyst containing both urea and sulfinamide functionalities functioned as an efficient ligand in promoting the indium-mediated allylation of acylhydrazone (Scheme 276).483 Various benzohydrazones derived from aromatic aldehydes were allylated with high enantioselectivities. Relying on crystallographic analysis of the ligand, the authors suggested that an intramolecular hydrogen bond between the NH group of the sulfinamide and the CO function of the urea may help to increase the Lewis acidity of the urea functionality and/or to rigidify the catalyst structure, thus facilitating the addition of allylindium to the CN bond. In addition, the poor enantioselectivities (96% de (when R = Bn), which can be explained by a Felkin−Anh model. The highly enantiopure allenyl alcohols were later converted into 1-deoxy-D-erythro-2pentulose and D-erythro-2-pentulose after further transformation. Interestingly, by using >2 equiv of propargyl bromide and indium, further attack of the excess organoindium reagent formed on the resulting homopropargyl and allenyl alcohols can take place (Scheme 345).546 As reported by Chan, the use

Scheme 348

tin as the reaction mediator should be accelerated by the addition of Lewis acid, and only relatively low regioselectivity was observed. Only one regioisomer was afforded when indium was used, even without any special activation by Lewis acid.199 Upon further elaborations, the method can be employed for the assembly of an array of diversely functionalized spirocyclic oxindoles.548,105 Interestingly, by combining an indium-mediated propargylation of substituted β-bromovinylaldehydes with a palladiumcatalyzed Heck-type intramolecular cyclization, an array of 3methyl cyclopentenones were isolated as the only products (Scheme 349).549 Similarly, a recent work from Samanta, Kar,

Scheme 345

of 2.2 equiv of γ-substituted propargyl bromide in the presence of either 30 mol % of InBr3 or ultrasonication in THF led to the formation of the corresponding products in moderate yields. In comparison, suppression of formation of the desired product was observed when the reaction was performed in aqueous media. The products were suggested to form via further attack of the propargylindium species on the first-formed allenyl alkoxylindium species. Thus, by directly reacting allenyl alcohol with propargyl bromide in the presence of In and InBr3 under ultrasonication, the regioselective allenylation or propargylation of allenyl alcohol was achieved as well (Scheme 346).

Scheme 349

Scheme 346 and Sarkar showed that a fast entry to hydroxyphenanthrene derivatives can also be gained by subjecting suitable β-furyl-α,βunsaturated aldehydes to indium-mediated propargylation followed by a gold(III)-catalyzed intramolecular Diels−Alder reaction of the resultant homopropargyl alcohols (Scheme 350).550 When methyl 2-(3-bromoprop-1-ynyl)benzoate was subjected to indium-mediated reaction with aldehyde, allenylation 338


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Scheme 350

Scheme 354

followed by an intramolecular cyclization occurred to give allenyl δ-lactone in yields between 51 and 98% (Scheme 351).551 The reaction worked well with both aromatic and

allenyl alcohol product bearing a bicyclic ring system was readily constructed in 82% yield with 16:1 dr upon exposure of the substrate to indium and HOAc in THF/H2O.88 Attempts to use other metallic systems (e.g., Zn, Bi, or SnCl2) led to either poor yield or low diastereoselectivity of the desired product. In a similar fashion, substrates containing both propargyl bromide and aldehyde moieties underwent intramolecular allenylation with the best diastereoselectivity of 3.6:1, using indium as the reaction mediator in the presence of AcOH (Scheme 355).554 In this case, DMF was proven to be the optimal solvent for the transformation at −40 °C.

Scheme 351

Scheme 355

aliphatic aldehydes in aqueous ethanol in the presence of HCl. In addition, glyceraldehyde, which contains a free hydroxy group, can be directly used to give the target product in 63% yield. This convenient method for the synthesis of allenyl δlactone potentially provides a basis for the construction of Bergenin and related compounds.552 Bromobutynyl-tethered benzaldehyde, readily prepared from salicylaldehydes and 1,4-dibromo-2-butyne, can also undergo intramolecular cyclization upon treatment with indium (Scheme 352).553 After surveying different solvents and acidic

In 1993, Whitesides and co-workers reported the indiummediated direct allenylation of unprotected carbohydrate of Dribose using 1-bromobut-2-yne. Akin to the indium-mediated allylation of α-hydroxyaldehydes in aqueous media, the reaction proceeded in aqueous EtOH to exclusively give allenyl-type product with good diastereoselectivity (8:1 syn/anti, Scheme 356).86 The preferential formation of syn-diols can be

Scheme 352

Scheme 356

additives, the intramolecular allenylation was found to proceed smoothly with added AcOH in DMF or aqueous DMF, giving the allenyl chromane derivatives in acceptable yields. The variant using bromobutynyl-tethered imine as substrate also proceeded in a similar manner with good efficiency (Scheme 353).185 More recently, Bates and Sridhar demonstrated the usefulness of the indium-mediated intramolecular allenylation in the synthesis of the nature product, (±)-Stemoamide, as well as the tetracyclic core of Stenine. As shown in Scheme 354, the

rationalized by a chelated transition state between the propargylindium or allenylindium intermediate and the αhydroxy group. In 1998, Li and co-workers also developed the indium-mediated coupling of 1-phenyl-3-bromopropyne with hydroxyaldehyde and lactol (Scheme 357), both bearing a Scheme 357

Scheme 353

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Scheme 358

neighboring hydroxy group, with high diastereoselectivities.87,555 Implementation of this highly diastereoselective allenylation toward the total synthesis of (+)-Goniofufurone, commencing from D-glucurono-6,3-lactone, was accomplished (Scheme 358).87,555 Likewise, hydroxy-bearing tetrahydrothiophene-3-carbaldehydes coupled efficiently with γ-substituted propargyl bromides in the presence of indium and ammonium chloride in aqueous media to furnish the final products with exclusive regio- and stereoselectivities (Scheme 359).104 Only allenyl-type products

Scheme 361

auxiliary in the substrate, the organoindium reagent generated only attacks from the less hindered side of the azetidine-2,3diones, giving rise to the allenyl alcohol as a single regio- and diastereoisomer.200,201 In contrast, the use of parent propargyl bromide led to the two regioisomeric homopropargyl and allenyl alcohols, although the diastereoselectivities were excellent. The products obtained can be easily converted into a number of spirocyclic β-lactams.556 Alcaide and co-workers found that enantiopure 4-oxoazetidine-2-carbaldehydes efficiently participated in allenylation with propargylindium reagent. The in situ-generated organoindium reagent from the reaction of indium with γ-substituted propargyl bromide reacted efficiently with 4-oxoazetidine-2carbaldehydes in aq. NH4Cl and THF, leading to the exclusive formation of allenyl alcohol with a high level of stereocontrol (>90:10 dr, Scheme 362).201,557 The products were demonstrated to be useful precursors for the synthesis of strained tricyclic β-lactams containing a cyclobutane ring.558

Scheme 359

were formed. In addition, the product was a 1,3-syn-diol, implying that free hydroxy group on the substrate did not get involved in the transformation via a Cram 1,3-indium-chelated transition state. Instead, the reaction proceeded by adopting a Felkin−Anh transition state; otherwise, a 1,3-anti-diol should be produced as the final product. In contrast, poor yields and relatively low diastereoselectivities were obtained when tin and zinc were used as reaction promoters. The substrate also can undergo an indium-mediated allylation in aqueous media with moderate yield and excellent stereocontrol. During the course of the synthesis of a trans-hydrindane ring system, Khan and co-workers exploited the reaction of tetrabromo norbornyl aldehyde with propargyl bromide mediated by indium in DMF (Scheme 360).382 Although exclusive formation of homopropargyl alcohol was observed, the diastereoselectivity obtained was rather low (60:40 dr). The indium-mediated reaction of γ-substituted propargyl bromide and enantiopure azetidine-2,3-diones bearing a chiral auxiliary also proceeded with excellent stereocontrol in a mixture of aq. NH4Cl and THF (Scheme 361). Owing to considerable steric repulsion from the neighboring chiral

Scheme 362

Analogous to the enantioselective indium-mediated allylation of aldehyde using (−)-cinchonidine400−402 and (1S,2R)-(+)-2amino-1,2-diphenylethanol405−407 as chiral ligands, the indiuminduced asymmetric propargylation of aldehyde with the parent propargyl bromide can also be achieved by using these two chiral promoters. As reported by Loh, up to 85% ee of the corresponding homopropargyl alcohol was obtained by using (−)-cinchonidine in THF/hexane (Scheme 363).559 However, almost no asymmetric induction was detected with the use of γsubstituted propargyl bromide under the conditions. Meanwhile Singaram et al. showed that, with the aid of (1S,2R)(+)-2-amino-1,2-diphenylethanol as chiral promoter, an improved enantioselective propargylation of aldehyde can be achieved (Scheme 364).560 Under the optimized conditions,

Scheme 360

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Scheme 363

Scheme 367

Scheme 364 homocoupling of imine and formation of the corresponding hydrolyzed product. Moreover, a cosolvent system of THF/ H2O turned out to be superior to the use of pure water or THF as the reaction medium. When aryl nitrile oxide was treated with propargyl bromide in the presence of indium in aqueous media, an allenylation followed by intramolecular cyclization occurred to give 5methylisoxazole in good yield (Scheme 368).564 In comparison, the reaction using magnesium as mediator proceeded in THF in a totally different way, mainly leading to 5-butynylisoxazole.

the desired homopropargyl alcohols were produced in 53−90% yields with 74−95% ee. It should be mentioned that a stoichiometric amount of chiral ligand should be used in both cases, which makes the protocols somewhat less attractive for scale-up purposes. NMR investigation suggested the possible formation of allenylindium(III) species in the reaction. Very recently, Pulukuri and Chakraborty applied the method to the use of (R)-Garner aldehyde, leading to the desired product in 10:1 anti/syn selectivity (Scheme 365). The obtained homopropargyl alcohol was subsequently utilized in the synthesis of the entire carbon framework of an actin-binding dimeric macrolide rhizopodin.561

Scheme 368

Recently, Jin and Xu developed a highly diastereoselective indium-mediated allenylation of chiral (S)-N-tert-butanesulfinyl imino ester by propargyl halides. The reactions worked efficiently in the presence of NaI in aqueous media, leading to various highly optically active α-allenylglycines (95−99% de, Scheme 369).565 By taking advantage of the unique reactivity of allene functionality, several challenging cis-substituted proline derivatives could be conveniently accessed.

Scheme 365

Scheme 369 Indium-mediated propargylation of acyl cyanide using propargyl bromide occurred regioselectively in aqueous media to afford either allenyl ketone or homopropargyl ketones (Scheme 366).562 Different from the general observations in Scheme 366

Lee and co-workers reported that [3R(1′R,4R)]-(+)-4acetoxy-3-[1′-(tert-butyldimethylsilyloxy)ethyl]-2-azetidinone, a typical chiral representative of 4-acetoxy-2-azetidinone, efficiently reacted with organoindium reagents generated in situ from indium powder and γ-substituted propargyl bromides in the presence of KI in DMF to selectively produce 4-allenyl-2azetidinones in good to excellent yields with excellent stereocontrol (Scheme 370).566 The allenyl-type products can be readily transformed into the corresponding bicyclic βlactams upon exposure to 5 mol % AuCl3. In line with the 1,4-addition of allylindium sesquihalide to 3tert-butyldimethylsilyloxyalk-2-enylsulfonium salt,489 propargylindium and allenylindium species can also undergo the same

most cases, in this reaction use of the parent propargyl bromide led to the formation of allenyl ketone, whereas the use of γsubstituted propargyl bromide resulted in the production of homopropargyl ketone. Similar to the propargylation of aldehyde, indium-promoted propargylation of imine and nitrone can also work in aqueous THF (Scheme 367).563 The use of Bu4NBr was found to be essential for product formation; otherwise, no reaction occurs. In addition, the addition of Bu4NBr appeared to inhibit the 341


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Scheme 370

Scheme 373

type of reaction with the preformed 3-tert-butyldimethylsilyloxyalk-2-enylsulfonium salt (Scheme 371). Understandably, the

Scheme 374

Scheme 371

catalysis, leading to the expected 1,5-enyne in good yield.518 In cases where vinyl allene was obtained as the product, it can be further transformed into a cyclic compound having an exomethylene group after undergoing subsequent Diels−Alder reaction with a symmetrical or unsymmetrical dienophile.570 Most interestingly, when α-halo or α-pseudohalo vinyl compound was subjected to the same protocol, the first-formed vinyl allene may, in the presence of palladium catalyst, undergo further [4 + 2]- or [4 + 4]-homocoupling depending on the identity of the R substituent (Scheme 375).571,572 Thus, various

use of α- or γ-substituted propargyl bromide led to formation of the corresponding silyl enol ether, bearing a propargyl or allenyl substituent, respectively, in reasonable yields. In addition, the use of TMSCl as reaction additive also effected the transformation with moderate to good performance.488 Interestingly, the resulting silyl enol ether products bearing a propargyl or allenyl substituent were able to undergo a W(CO)5(THF)- or W(CO)5-catalyzed intramolecular cyclization to give the corresponding cyclopentene derivatives in good yields.567,568 Lee and co-workers discovered that organoindium reagents derived from propargyl bromide can also undergo palladiumcatalyzed cross-coupling with various organohalides.569 The cross-coupling occurred efficiently in the presence of 4 mol % of Pd(PPh3)4 and 3 equiv of LiI in DMF at 100 °C, furnishing allenes regioselectively in good yields. This is irrespective of the substitution pattern of the propargyl bromide used (Scheme 372). In addition, polyhaloarenes can be functionalized in a similar manner to give either polyallene or unsymmetrical bis(allenes) (Scheme 373). The latter can be prepared by the sequential treatment of dihaloarenes with two different types of propargyl bromide under optimal conditions (Scheme 374). Allyl carbonate can also be used as an electrophilic coupling partner to react with propargylindium reagent under palladium

Scheme 375

Scheme 372

eight-membered carbocycles can be easily synthesized through the palladium-catalyzed two-step sequence, involving first a cross-coupling followed by a [4 + 4]-cycloaddition, commencing from α-bromovinyl arenes and propargyl bromides. When the above reaction was carried out in the presence of carbon monoxide, 3,7-nonadienone derivatives were produced as well. Additionally, if the resulting eight-membered carbocycles were simultaneously treated with suitable dienophiles, a further [4 + 4]-cycloaddition can occur leading to the rapid assembly of bicyclo[6.4.0]dodecenes in a highly efficient, one-pot manner. Very recently, Ma and co-workers developed a highly efficient method for the construction of dihydrocycloocta[b]indoles starting from 2-allyl-3-iodoindoles and propargyl 342


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α-Chlorosulfide species are also suitable candidates capable of undergoing indium-mediated reactions with carbonyl compounds.110,111 Among them, α-chloropropargyl phenyl sulfide is a special case worthy of emphasis. It reacted with various aldehydes in pure water or in aqueous DMF to give the corresponding hydroxy sulfides in reasonable diastereoselectivities with the retention of the alkynyl moiety (Scheme 378).

bromides (Scheme 376).573 The one-pot reaction was performed in the presence of indium, LiI, Pd(OAc)2, P(2Scheme 376

Scheme 378

Generally, anti-hydroxy sulfides were afforded as the major diastereomers. Interestingly, in cases where InCl3 was used as the reaction additive, syn-hydroxy sulfides were produced predominantly, possibly because of the chelation of the indium(III) salt to the sulfur and oxygen heteroatoms. In contrast, the use of Rieke magnesium or n-BuLi as the reaction promoter led to a mixture of alkynyl- and allenyl-type products. The thus-formed hydroxy sulfides can be conveniently converted into the corresponding alkynyl epoxides without the loss of syn/anti selectivity. When propargyl aldehydes were used as coupling electrophiles, the coupling reactions performed better in NMF than in water; the generated products are interesting synthetic precursors to epoxydiynes and enediynes.581 Lee and co-workers have developed an efficient approach for the synthesis of synthetically useful vinyl allenols via the reaction of carbonyl compound with γ-vinyl propargyl bromide (1-bromopent-4-en-2-yne) (Scheme 379).89 The reaction using

furyl)3, and 4 Å molecular sieve in DMF at 100 °C. An initial palladium-catalyzed formation of allene followed by [1,5]hydrogen migration and electrocyclization was most likely the reaction pathway. The usefulness of this coupling/cyclization sequence was demonstrated in the synthesis of Iprindole. In comparison to organoindium reagent derived from propargyl halide, organoindium species prepared from gemdifluoropropargyl bromide exhibited unique reactivities toward a diversity of electrophiles (e.g., aldehyde, imine, and bromine), affording various gem-difluoro-containing alkynes and allenes depending on the nature of the electrophiles (Scheme 377).574 Scheme 377

Scheme 379

Among these, it is worth noting that its reaction with aldehyde can be performed effectively in aqueous media. With the exception of aqueous formaldehyde, which reacted to give allenyl alcohol as the major product upon prolonged reaction time,574,575 substituted aldehyde reacted at the α-position of the gem-difluoropropargyl bromide exclusively to afford homopropargyl alcohols under appropriately selected conditions.280,574,576,577 The latter can be further transformed into other useful molecules.575,576 Additionally, the corresponding gem-difluoroallenyl bromide, readily accessible from the reaction of gem-difluoropropargyl bromide with bromine in the presence of indium, behaved as a gem-difluoromethylene cation and underwent substitution with a variety of nucleophiles.578 A systematic study based on NMR, X-ray, etc. indicated the formation of an organoindium(III) species in the reactions, possibly through the intermediacy of an organoindium(I) species.48,579 Later, this chemistry of the propargylation of aldehyde was applied by Qing and co-workers to the synthesis of several gem-difluoro-containing organic molecules.580

indium proceeded smoothly in the presence of LiI in THF, forming mainly vinyl allenol in good yields. Acetophenone could also be used to give moderate yield (45%) of the product. In comparison, the utilization of other metals such as magnesium and zinc gave comparatively low conversion to the expected product. The versatility of the vinyl allenols obtained was demonstrated in the synthesis of functionalized dihydrofuran, cyclohexene, and 2-halo-1,3-diene derivatives by treatment of the vinyl allenols with a gold catalyst, dienophile, and indium(III) halide, respectively. The indium-mediated allenylation of aldehyde using ethyl 4bromobutynoate was also established by Lee and co-workers, which for most cases provided the corresponding αhydroxyalkyl allenyl ester regioselectively in good yields (Scheme 380).582 Similarly, the product formation was considerably accelerated by the addition of LiI as reaction additive in DMF. The use of another solvent system such as 343


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isomerization to give synthetically valuable indolizines in 57− 83% yields in a one-pot operation (Scheme 382).589 Notably,

Scheme 380

Scheme 382

the presence of carboxyl group in ethyl 4-bromo-2-alkynoate is critical for the efficient progress of the reaction; otherwise, no occurrence of such tandem cycloaddition was observed. Homoallenylindium reagents, generated in situ through the reaction of indium with 4-bromo-3-[(trimethylsilyl)methyl]1,2-butadiene, also reacted with a variety of aldehydes in DMF to produce 2-(2-hydroxyethyl) homoallenylsilanes in good to excellent yields (Scheme 383).590,591 Aldehydes containing

THF and aqueous media resulted in only moderate to low yields. As anticipated, aromatic aldehyde possessing acidic hydroxy group can be used without complication as well. Under gold catalysis, those α-hydroxyalkyl allenyl esters readily undergo intramolecular cyclization to provide facile entry to ethyl 2-naphthoate derivatives582 or 2-alkyl and aryl-3ethoxycarbonyl-2,5-dihydrofurans,583 depending on the nature of the R substituent. Also, the α-hydroxyalkyl allenyl esters obtained can be readily converted into 3-ethoxycarbonyl-2halo-1,3-dienes584,585 and (E)-α-ethynyl-α,β-unsaturated esters.586,587 Organoindium reagents derived from the insertion of indium with ethyl 4-bromo-2-alkynoates are also amenable to crosscoupling reactions with aryl iodides or vinyl triflates in the presence of 2 mol % of Pd2(dba)3·CHCl3, 16 mol % of P(pCF3C6H4)3, and NaI (1.5 equiv) in THF at 70 °C, selectively producing ethyl 2-aryl-2,3-alkadienoates in moderate to good yields (Scheme 381).112 The choice of THF as solvent and

Scheme 383

acidic hydroxy and carboxyl groups were also amenable to the mild reaction conditions. However, no reaction occurred with the use of a ketone substrate. It is worth noting that the reaction worked equally well in water. In a related report, Lee and co-workers also described an efficient method for the synthesis of a similar organoindium reagent via the reaction of indium with allenylmethyl bromide (Scheme 384).592 Interestingly, its subsequent cross-coupling

Scheme 381

Scheme 384

electron-poor phosphine ligand of P(p-CF3C6H4)3 were critical for the success of the transformation. The mild reaction conditions make the protocol compatible to functionalities including NO2, CHO, Ac, COOEt, CONHBn, etc. In comparison, other metals such as Mg and Zn cannot work under the same conditions. Upon exposure of the resultant products to AuCl3 and AgOTf in the presence of AcOH or TfOH, an intramolecular ring-closure took place to generate αaryl γ-butenolides in reasonable yields.588 Interestingly, when 2pyridyl triflates or iodides were utilized as electrophiles, the in situ-generated allene intermediates from palladium-catalyzed cross-coupling can undergo further palladium-catalyzed cyclo-

reaction with aryl halides under palladium catalysis produced 1,3-butadienes in good yields. A tandem one-pot, two-step cross-coupling of organoindium reagent with aryl halide followed by a Diels−Alder cycloaddition sequence for the synthesis of six-membered cyclohexenes was achievable as well. A reverse but similar sequence for the construction of diverse 1,3-butadienes by treating organoindium reagent (generated in situ from insertion of indium into 1-bromo-2,3-butadiene) with dienophiles followed by palladium-catalyzed cross-coupling of the resultant 1-cyclohexenyl-1-indium intermediate with organohalide was accomplished as well in a one-pot fashion (Scheme 385).593 Formation of a 1-cyclohexenyl-1-indium intermediate was proven. 344


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invoking the formation of another organoindium intermediate B in the second propargylation step, with chelation of the allenylindium to the oxygen of the newly generated indium alkoxide. By a similar token, the indium-mediated reaction between isatin and 1,4-dibromo-2-butyne in aqueous THF also took place to produce 3-(1,3-butadien-2-yl)-3-hydroxy-1-methylindolin-2-one in 44% yield (Scheme 389).199

Scheme 385

Scheme 389 When 1,4-dibromo-2-butyne was subjected to indiummediated reaction with carbonyl compounds in water, synthetically useful 1,3-dieneyl alcohols were obtained in acceptable yields (Scheme 386).594 The formation of a di-indium species Scheme 386 A high level of asymmetric induction was attained in the reaction of 1,4-dibromo-2-butyne and 1,4-bis(methanesulfonyl)-2-butyne with optically pure azetidine-2,3diones (Scheme 390).201,596 However, while excellent diasterScheme 390

was proposed to be the reactive reaction intermediate. The existence of this di-indium intermediate was somewhat proven through the formation of a seven-membered ring via a doubleaddition under the reaction conditions (Scheme 387). Scheme 387

eoselectivities were observed for the reaction, only low to moderate yields were obtained. The resulting 2-azetidinonetethered 1,3-butadiene products can be transformed with ease into more complex molecules via an ensuing Diels−Alder reaction with suitable dienophiles. Analogously, organoindium reagent generated in situ from indium and 1,3-dibromo-2-butyne also effectively coupled with various imines in the presence of MgSO4 in ethanol to give 2aminomethyl-1,3-dienes in good yields (Scheme 391).597 By using AcOH as the acidic additive, the procedure can also be developed into a one-pot process, through the direct use of aldehydes and amines as starting materials. Ensuing Diels− Alder reactions of the obtained 1,3-dienes possessing an

Interestingly, when the same reaction was performed using 2 equiv of aldehyde in the presence of ZnF2 in THF, a highly stereoselective formation of trans-acetylenic diol was achieved (Scheme 388).595 On the basis of NMR investigation, a butadienyl di-indium(III) complex A was suggested to be the active intermediate formed before the first allenylation. The excellent diastereoselectivities observed can be rationalized by Scheme 388

Scheme 391

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aminomethyl group with dienophiles provided valuable adducts having 6-membered carbocycles at α-position.598 Also, 4-acetoxy-2-azetidinones, as the synthetic equivalent of imine, can undergo coupling with organoindium reagents generated in situ from indium and 1,4-dibromo-2-butyne in the presence of LiCl in DMF. This reaction produces 2azetidinones selectively, which contain a 1,3-butadienyl-2-yl group at the C4-position (Scheme 392).599 Further function-

Scheme 394

Scheme 392

with silver nitrate under basic conditions in aqueous acetone, an insoluble silver acetylide species was formed that can be separated from the allenyl alcohol with ease through a simple filtration. The homopropargyl alcohol can subsequently be regenerated by hydrolyzing the silver acetylide species isolated with aq. HCl (1 M). Finally, like the allylation reaction, the indium-mediated propargylation and allenylation of electrophiles, such as 1,2dicarbonyl compounds,60b,246,250,387 β-chloro vinylaldehyde,160 acetal and ketal,266 phenacyl bromide,257 α-diazoketone,255 glycal,71 α-imino ethyl ester,180 imino isatin,202 epoxide,522 quinolinium and isoquinolinium salts,182,529 organosilyl chloride,536 thiocyanate,533 hydroxyphthalide,184 and others,159 have also been reported.

alization of the products obtained by means of coupling with a variety of dienophiles furnished functionalized 2-azetidinones with a cyclohexenyl moiety at the C4-position. Organoindium reagent generated in situ from indium and 1,6-dibromo-2,4-hexadiyne in the presence of LiI in THF seemingly behaves as the 3,6-dianion of 1,2-hexadien-4-yne. It can undergo a coupling reaction with carbonyl compounds to selectively furnish 1,6-diols possessing an allenyne unit in satisfactory yields (Scheme 393).600 Functional groups such as hydroxy and carbonyl groups were compatible with the mild reaction conditions.

4. INDIUM ENOLATE 4.1. Introduction and Preparative Method

Indium enolates are usually prepared in situ from the reaction of α-halo carbonyl compounds with indium in organic solvents such as THF, DMF, and Et2O and may exist as an equilibrium mixture of the C- and O-enolates (Scheme 395).36,603 In most

Scheme 393

Scheme 395

cases, α-bromo and α-iodo carbonyl compounds are chosen as substrates. The preparative method can also be extended to include the use of InX210 as metallic species and α-halo nitrile604 as well as 1-bromo-1-nitroalkane605 as substrates (Scheme 396). In addition, the transmetalation of lithium enolate with indium(III) trichloride offers another viable route to indium enolates.606

Similarly, 4-acetoxy-2-azetidinones was also able to undergo reaction with organoindium reagent generated in situ from indium and 1,6-dibromo-2,4-hexadiyne. Of special interest is that, in this case, 6-dibromo-2,4-hexadiyne acted as a 3-anion of 1,2,4,5-hexatetraene, reacting with 4-acetoxy-2-azetidinones in the presence of LiCl in DMF to selectively produce 2azetidinones possessing a 1,2,4,5-hexatetraen-3-yl group at the C4-position (Scheme 394).601 Valuable aryl-functionalized 3alkyl-4-phenylazetidin-2-ones can be eventually produced in good yields by tandem sequencing this methodology with the Diels−Alder reaction, followed by subsequent aromatization. In most cases, the generation of a mixture of homopropargyl and allenyl alcohols in reactions using propargyl halide and the difficulty in their separation limited their applications in organic synthesis. More recently, a simple approach to separate homopropargyl alcohol from allenyl alcohol was developed by Loh and co-workers.602 By treating homopropargyl alcohol

Scheme 396

In actual fact, the most well-known organometallic species derived from α-halo ester is the zinc enolate, and its reaction with aldehyde to give β-hydroxyester is referred to as the Reformatsky reaction.607,608 Its tolerance to ester functional groups makes zinc enolate an important complement to the more reactive organomagnesium and organolithium reagents. 346


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By the same token, the modified Reformatsky-type reaction using indium enolates was also found to tolerate functional groups such as ester and alcohol. In 1975, Rieke reported the first Reformatsky-type reaction of aldehyde with indium enolate derived from the insertion of activated indium into α-halo ester.36 Subsequent work from many other groups suggested that the reaction also proceeds well using commercially available indium powder to afford βhydroxyester selectively, without the formation of α,βunsaturated ester elimination byproduct during the process. Nevertheless, when α-halo ketone is selected as substrate, the indium-mediated dehalogenation of α-halo ketone (especially in protic solvents such as methanol and water)609−611 and its homocoupling may constitute the major side-reactions.612 In addition, several types of organoindium species were suggested to be the reactive organometallic species formed in such Reformatsky-type reaction, typically diorganoindium(III) monohalides (R2InX, R = CH2COOR′),36 organoindium(III) sesquihalide (R3In2X3),603 and organoindium(I),613,614 while organoindium dihalide (RInX2) is most likely to be the reactive species formed in reactions involving InX as mediator.210

Scheme 398

the yield of product, an organoindium sesquiiodide was proposed to be the active species involved in the reaction. Later, Butsugan, Araki, and co-workers demonstrated that the above reaction involving α-iodo carbonyl compound also can be carried out with similar efficiency by employing 1.2 equiv of InI as reaction mediator.210 However, α-bromo ester failed to undergo this reaction. An organoindium diiodide species (RInI2) appears to be the reactive organoindium intermediate formed in the reaction. Ultrasonication was found to considerably improve the efficiency of indium-mediated Reformatsky reaction, in terms of both reaction rate and product yield. As reported by Lee and co-workers, α-bromo ester reacted with a wide variety of carbonyl compounds under ultrasonication to give the desired product in good to excellent yields.615,616 THF is the solvent of choice, and attempts to perform the same reaction in aqueous media proved futile. Relatively sterically hindered substrates such as ethyl 2-bromopropanoate and ethyl 2-bromo-2methylpropanoate worked equally well under optimized conditions, and use of the former substrate led to the desired product with a moderate diastereoselectivity of 2.5:1. Later, Soengas's group also extended the ultrasound-irradiated method to the use of paraformaldehyde and 2-bromolactones as substrates.617 In addition to the use of organic solvents, a solvent-free technique was also applied in indium-mediated Reformatsky reaction. Remarkably, a survey of organic solvents revealed that the reaction performed under solvent-free conditions is superior to the same reaction carried out in conventional organic solvents such as THF and DMF, giving rise to βhydroxyester in fairly high yields.618 Besides the classical method for the synthesis of indium enolate from insertion of indium into α-halo ester, indium enolate preparation can also be accessed via the transmetalation of lithium enolate with indium(III) trichloride. As reported by Araki and co-workers, indium enolate can be easily prepared by treating 3 equiv of alkyl acetate with 3 equiv of lithium diisopropylamide (LDA) followed by the addition of 1 equiv of InCl3 (Scheme 399).606 The indium enolate generated subsequently cross-coupled with various aldehydes to deliver β-hydroxyester in good yields, although the anti/syn selectivities were low in cases where two stereogenic centers were produced. When methyl 2-bromoacetate was subjected to the above sequence, a Darzens-type epoxide product was unexpectedly yielded (Scheme 400).

4.2. Application in Organic Synthesis

As mentioned above, the first key development in the application of indium enolate in organic synthesis was reported by Rieke in Reformatsky-type reaction of α-bromo ester with aldehyde in 1975 (Scheme 397).36 Activated indium, also Scheme 397

known as Rieke indium, which can be accessed from the reduction of InCl3 by potassium in refluxing xylene, was used to realize the transformation. The resultant indium enolate generated from the insertion of activated indium into αbromo ester underwent efficient reaction with aldehyde, as well as ketone in xylene or ether, giving the corresponding βhydroxyester in modest to excellent yields. It is noteworthy that this activated indium also allowed the use of less reactive αchloro ester as substrate, reacting with cyclohexanone with modest efficiency (42% yield), whereas the analogous reaction using commercial indium proceeded sluggishly even with prolonged reaction time (maximum 17% yield). Information collected by the authors suggested the formation of an indium enolate with a formulation of (CH2COOR)2InBr. In 1988, contributions from Araki and co-workers revealed that commercially available indium worked equally well in Reformatsky reaction by using the more reactive α-iodo ester and performing the reaction in THF (Scheme 398).603 Both aldehyde and ketone were proven to be suitable candidates, albeit moderate yield was obtained with the use of ketone. Aliphatic aldehyde, which reacted poorly in Rieke’s protocol, exhibited high performance in this approach. Notably, cinnamyl aldehyde underwent exclusive 1,2-addition at its formyl group in 89% yield, while salicylaldehyde bearing a free hydroxy group can be directly employed in the reaction without prior derivation in 67% yield. On the basis of investigation on the effect of the molar ratio of aldehyde/α-iodo ester/indium on 347


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the incompatibility of the in situ-generated zinc enolate with the hydroxy group embedded in the chiral ligands. Lactones can also be modified through an indium-mediated Reformatsky reaction with ethyl α-bromoisobutyrate under ultrasonication, leading to the corresponding ketals in satisfactory yields (Scheme 403). The protocol was also applicable to the functionalization of sugar lactones, giving rise to ulosonic acid esters with remarkable chemoselectivity.621−623

Scheme 399

Scheme 400

Scheme 403

Intriguingly, Schick and co-workers90,619 found that, when the highly substituted ethyl α-bromoisobutyrate was selected as substrate, its reaction with ketones afforded α,α,β,β-tetrasubstituted β-lactones as the major product in acceptable yields, most likely arising from spontaneous cyclization of the in situformed β-hydroxyester intermediate (Scheme 401). The Scheme 401

Baba and co-workers established a diastereoselective Reformatsky reaction of aryl ketone with branched α-bromo ester.613,614 In most instances, the reaction proceeded effectively in the presence of either indium or indium(I) halide, to give the desired product with nearly 80:20 dr favoring the anti-isomer (Scheme 404). A six-membered ring transition state involving an (E)-enolate was proposed to account for the predominant production of the anti product.

reactions were carried out in the polar solvent, DMF, using either sacrificial indium anode under electrolysis or conventional indium powder with stirring. Negligible, if any, Reformatsky-type ethyl β-hydroxyester product was observed under these conditions. However, when the ketone was replaced by an aldehyde or the ethyl α-bromoisobutyrate was replaced by an unbranched ethyl α-bromoalkanoate, exclusive generation of the ethyl β-hydroxyester was observed. In comparison, the use of zinc as reaction activator led to relatively low conversion to the desired product. A later study from the same group implied that the reaction scope can be further expanded to the synthesis of di-, tri-, and tetrasubstituted β-lactones from both ketone and aldehyde, by employing phenyl α-bromoalkanoates as substrate, which bears a better phenoxide leaving group.620 To date, the only available method associated with the enantioselective indium-induced Reformatsky reaction using chiral ligand was reported by Johar, Araki, and Butsugan in 1992 (Scheme 402).73 After surveying several chiral ligands, cinchonine and cinchonidine emerged as the two most effective ligands for chiral induction, furnishing optically active αhydroxyesters in 42−71% ee. The reactions were carried out in THF/pentane in the presence of a stoichiometric amount of the chiral ligand and were only effective for aryl aldehydes. Replacement of indium with zinc was met with failure, due to

Scheme 404

In the meantime, the same group also developed a highly syn-selective Reformatsky reaction of α-iodo ester with ketone bearing an α-alkoxy group (Scheme 405).614 The choice of reaction conditions is critical for obtaining excellent diastereoselectivity. Their findings revealed that excellent diastereoselectivity of 98:2 in favor of the syn diastereomer can only be achieved by carrying out the reaction in nonpolar toluene solvent under ultrasonication, and in the presence of indium(I) halide (or generated in situ by mixing indium with indium(III) halide). The sole use of indium or indium(III) halide as

Scheme 402

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Scheme 405

Scheme 407

product, while the use of protic solvent (MeOH or H2O) resulted in the preferential formation of the syn product. Currently, causes leading to this startling diastereoselectivity difference cannot be fully understood. It should be noted that the generated dihaloindium hydride might reduce the aldehyde to some extent; thus, 10−30% of benzyl alcohol was formed as reaction byproduct, depending on the aldehyde used. Under solvent-free conditions, a Reformatsky-type reaction of α-bromo ester with imine at room temperature also proceeded well to furnish the desired β-aminoester product in good yield (Scheme 408).618 When ethyl 2-bromopropanoate was used, the corresponding product was obtained without any diastereoselectivity bias (1:1 dr).

reaction promoter, or performing the reaction in strong chelating THF solution, led to poor reaction performance. Evidently, the chelation-controlled transition state involving the neighboring α-alkoxy group in the ketone substrate is the leading cause of the syn selectivity observed. On the basis of the unique behavior of the reaction, a low-valent organoindium(I) intermediate [RIn(I), R = CH2COOEt] was postulated to be the reactive species in this Reformatsky-type reaction. Following the success of that work, Baba and co-workers established an efficient method for the synthesis of lactones starting from α-hydroxyketones and branched α-bromo ester. In this reaction the stereocontrolled construction of three contiguous stereogenic centers was achieved (Scheme 406).624

Scheme 408

Scheme 406

When the same reaction was carried out in THF at an elevated temperature of 80 °C, the resulting β-aminoester intermediate spontaneously cyclized to give β-lactams in moderate yields (Scheme 409).626 In some cases, the desired Scheme 409 It should be mentioned that ultrasonication in water is required to achieve complete conversion of the acyclic product to the desired lactone via a transesterification pathway. In contrast, the use of α-alkoxyketone or β-hydroxyketone in place of the αhydroxyketone resulted in either poor diastereoselectivity or no product formation. The relative syn-stereochemistry about C1− C2 in the lactone product indicated the involvement of strong chelation during the transition from reactant to product. Hence, a boat-type chelated bicyclic transition state was invoked to account for the excellent diastereoselectivity observed in the reaction. When enone was treated with dihaloindium hydride (HInX2), a reactive species in situ-generated by mixing indium(III) halide with Bu3SnH, an indium enolate intermediate could be generated via 1,4-addition reaction. With the coexistence of aldehyde in the reaction mixture, the resulting indium enolate may undergo an aldol-type reaction with the added aldehyde. As shown in Scheme 407, the one-pot reaction proceeded well with aromatic aldehyde under optimized conditions to give the corresponding aldol product in reasonable yield.625 Most interestingly, the diastereoselectivity can be adjusted by utilizing different solvents. The use of aprotic solvent led to the predominant generation of anti

β-lactam products were contaminated with the corresponding uncyclized β-aminoester. No reaction occurred with the use of bulkier tert-butyl bromoacetate as reactant. Commencing from the corresponding ferrocenyl substituted imines, the method also allowed for the synthesis of ferrocenyl-substituted βlactams in 41−66% yields under similar conditions.627 A highly diastereoselective version of this strategy for the synthesis of enantiomerically enriched β-lactams, starting from sugar-derived imine, was developed by Soengas and co-workers (Scheme 410).628 Indium-mediated reaction of the sugarderived imine with α-bromo esters proceeded efficiently under ultrasonication to give the products with complete stereocontrol, favoring the syn-isomer. The chelation of organoindium species with both nitrogen and oxygen atoms may be the key factor in dictating the high selectivity. The products 349


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Scheme 410

Scheme 413

ether of the α,β-unsaturated ketone in satisfactory yields of 62− 74%. Another appealing alternative is using TMSCl as an additive. It was also capable of switching the addition of the organoindium reagent to enone from 1,2-addition to 1,4addition.488 Similarly, the method is also amenable to the 1,4addition of diethyl bromomalonate with various α,β-unsaturated ketones (Scheme 414).630 As explored by Lee and coworkers, the yields were generally good to excellent when the indium-mediated protocols were carried out in the presence of TMSCl in THF. Scheme 414 obtained can be further converted into the corresponding sugar-derived β-amino acids and azetidines. Enamine, especially in the presence of acid, can serve as an imine equivalent. Mosset and co-workers reported that, when enamine was exposed to 1 equiv of acetic acid, the equilibrium may shift to the side of the imine and thus undergo a Reformatsky-type reaction with methyl bromoacetate in the presence of indium to give the corresponding β-amino esters (Scheme 411).113 However, only low yields of the desired products were obtained.

Substituted allyl α-bromoacetates, upon exposure to a mixture of indium, indium(III) chloride, TMSCl, and Et3N under ultrasonication in an appropriate solvent, undergo an interesting Reformatsky−Claisen rearrangement to provide a carboxylic acid, bearing an α-quaternary center (Scheme 415).631,632 Debromination of the starting material constitutes the major side-reaction in this process.

Scheme 411

Scheme 415

para-Quinone may be functionalized using indium enolate derived from α-iodo ester. The reaction proceeded smoothly at room temperature in DMF to generate para-quinol esters, including naturally occurring jacaranone, in modest to excellent yields (Scheme 412).629

Although it was reported that an indium-mediated Reformatsky reaction using α-halo ester failed to work in aqueous media,291,616,618 Chan and co-workers observed that in reality the reaction could take place with some success.72 For example, benzaldehyde can react with substituted α-bromo esters in water to give the target products in moderate to low yields (Scheme 416). Generally, the products were obtained with poor erythro/threo selectivities (∼ 2.2:1 dr). It is worthy

Scheme 412

Scheme 416

Indium enolate can also undergo 1,4-addition to α,βunsaturated ketone in the presence of Me2S and TBSOTf (Scheme 413). As discussed earlier,489 the formation of an electrophilic 3-tert-butyldimethylsilyloxyalk-2-enylsulfonium intermediate, between the α,β-unsaturated ketone and the two additives, was the key to the success of such type of reaction. Thus, the in situ-generated α-indium ester reacts with the preformed intermediate to give the corresponding silyl enol 350


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to note that α-bromophenylacetic acid, bearing a free carboxyl group, could also be employed under these conditions to give the desired product in 37% yield. In addition, the use of optically active (S)-(−)-bromopropionic acid (88% ee) as substrate led to optically inactive product (erythro/threo 2.2:1), indicative of a possible radical-type mechanism involved in the reaction. More importantly, in the case of the reaction between 2-bromopropiophenone and benzaldehyde in water, although the use of indium resulted only in a slight improvement in yield, a pronounced increase in diastereoselectivity (erythro/ threo 12:1) relative to the same system using zinc and tin as reaction promoter was observed (Scheme 417).

Scheme 420

Scheme 421

Scheme 417 in mediating the reaction even in the absence of any activation. By mimicking the protocol, Medebielle and co-workers achieved the coupling of β-aminovinyl chlorodifluoromethyl ketones with a series of heteroaryl aldehydes in good efficiency (Scheme 422).633 In contrast, a similar reaction using an electrochemical method was found to be less efficient. Scheme 422 α-Halo ketones are also able to undergo indium insertion to generate the corresponding indium enolates.612 For example, when 2-iodoacetophenone was treated with indium in DMF at room temperature, the resulting indium enolate reacted with another molecule of itself to give an interesting Darzens-type β,γ-epoxy ketone product in 57% yield (Scheme 418). Small

Indium enolate generated from α-bromo ketone also reacted with sodium alkyl thiosulfate634a or diorganyl diselenide634b in aqueous media to give phenacyl sulfide and α-selenocarbonyl compounds, respectively (Scheme 423).

Scheme 418

Scheme 423 amounts of dehalogenation (acetophenone) and homocoupling (1,2-dibenzoylethane) byproduct were also isolated. When an aldehyde was introduced into the system, cross-coupling occurred to give mainly the β-hydroxyketone, as well as some elimination product (Scheme 419). Additionally, an efficient Scheme 419 Indium enolate derived from the reaction of indium with αbromo acetonitrile can also participate in the addition reaction. When aldehyde was used as the coupling partner, introduction of TMSCl as reaction additive is a prerequisite for success of the transformation, leading to the formation of β-hydroxynitrile in reasonable yields (Scheme 424).604 Later, the same approach was extended to the functionalization of protected “hexulose aldehyde”,92 and that exhibited better yields and diastereoselectivities compared to the same reaction using Zn−Cu couple.

method for the preparation of α,β-unsaturated ketones was also established by treating 2-bromoacetophenone or 1-bromoacetone with various aldehydes in the presence of indium(I) iodide in refluxing THF for 12−17 h (Scheme 420). In a similar manner, the activated chlorodifluoromethylcontaining compound, 2-chloro-2,2-difluoro-1-(furan-2-yl)ethanone, was proven by Welch and co-workers to be an appropriate substrate for an indium-mediated Reformatsky-type reaction in aqueous media. The reaction proceeded more efficiently in aqueous media than in organic solvent, giving the expected α,α-difluoro-β-hydroxyketone product in moderate yields (Scheme 421).91 In addition, indium was superior to zinc

Scheme 424

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When more reactive aromatic acyl cyanide was used as electrophile,635,636 the addition of TMSCl was not necessary (Scheme 425). However, the reaction was considerably

Scheme 429

Scheme 425

facilitated by ultrasonication to give the corresponding αcyano aryl ketones in 60−86% yields. Extension of this ultrasound-irradiated method to the use of ethyl bromoacetate was also feasible, leading to various β-ketoesters in 79−92% yields (Scheme 426).636

and the formation of a six-membered ring transition state may possibly be responsible for the stereoselectivity formed. α,αDihalo nitrile reacted in a same manner to deliver the corresponding 2-alkenenitrile; however, the conformation of the alkene cannot be controlled in this case.642 In a related but earlier study, Araki and Butsugan showed that α,α-dibromomethylene compounds containing two additional electron-withdrawing groups (CN or COOEt) exhibited unique reactivity toward electrophiles.643 When mixed with electron-deficient alkenes in the presence of indium, LiI, and DMF, cyclopropanation occurred to give cyclopropanes in 20− 100% yields (Scheme 430). Both LiI and DMF were

Scheme 426

Peppe and co-workers have demonstrated that stirring of α,α-dihalo- or α,α,α-trichloronitrile and ketone with indium(I) bromide in THF generated the corresponding reactive organoindium reagents in situ. These intermediates then spontaneously reacted with carbonyl electrophiles to give the corresponding products in moderate to good yields (Scheme 427).637−639 On the other hand, in the absence of carbonyl

Scheme 430

Scheme 427 indispensable for achieving good conversions. Acrolein could be used as well, whereas no reaction occurred with unactivated or electron-rich alkenes. Noteworthy is that a recent advancement from Peppe et al. showed that such cyclopropanation also can be achieved by using α,α-dichloroacetophenone as substrate and InBr as reaction mediator, leading to multisubstituted cyclopropanes, in most cases, with excellent stereoselectivities.644 Of special interest is the case when the above reaction using α,α-dibromomethylene compound was carried out in the presence of carbonyl electrophiles. Under the same conditions, 2,2-dibromomalononitrile reacted with carbonyl compounds to generate tetracyanocyclopropanes in 5−94% yields, presumably via the initial formation of an alkylidenemalononitrile intermediate followed by cyclopropanation (Scheme 431).

electrophile, α,α-dichloro ketone may undergo homocoupling to give 1,4-diketone as the reaction product (Scheme 428).640 Cross-coupling between two different α,α-dichloro ketones was also proven to be feasible.

Scheme 431

Scheme 428

Ethyl 2,2-dibromocyanoacetate underwent reaction with aldehydes in a totally different manner, furnishing Darzenstype oxirane products (Scheme 432). The formation of an indium carbenoid was suggested to be the reactive species in the reaction. Later, an analogous study employing α,αdibromomethylene compounds possessing only one electronwithdrawing group (CN or COOEt) was reported as well.158

Interestingly, when α,α-dihalo ketone was treated with 2 equiv of InBr in the presence of carbonyl electrophile in THF under refluxing, α,β-unsaturated ketone with a (E)-configuration of the newly generated C−C double bond was produced as product (Scheme 429).641 The reaction was proposed to proceed via the mechanism shown in Scheme 429, 352


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in the same manner as aldehydes to give 2-nitroamines in reasonable yields and diastereoselectivities.648 The present method served as an efficient alternative to the conventional base-catalyzed Henry reaction, which is plagued by relatively low yields and limited substrate scope. Finally, in addition to above examples, indium enolates generated from α-halo ester and α-halo acetonitrile were capable of reacting with electrophiles such as 1,2-dicarbonyl compound60b,246 and in situ-formed imine.446

Scheme 432

Soengas and Estévez also extended their ultrasound-assisted, indium-mediated Reformatsky-type reaction to the use of 1bromo-1-nitroalkanes. Their findings showed that the coupling of 1-bromo-1-nitroalkanes with aldehydes proceeded with equal success in the presence of indium under ultrasonication to afford various 2-nitroalkanols in moderate to good yields (Scheme 433).605 In addition, the method worked equally well

5. INDIUM HOMOENOLATE Homoenolate649,650 is a species that contains an anionic carbon β to a carbonyl group, which serves as a very useful threecarbon synthon for organic synthesis. Normally, metal homoenolate was synthesized via ring-opening of siloxycyclopropane with various metal halides (such as TiX4 or ZnX2) or by an oxidative addition of zinc to β-iodo esters. Although research concerning the development of different metal homoenolates (especially those of titanium and zinc homoenolates) has been well-established, the exploration on the synthesis of indium homoenolate has not been undertaken for a long time. In addition, previous research on metal homoenolate is mainly focused on carbonyl compounds of ester and amide rather than ketone, which might be due to the fact that metal homoenolate (particularly titanium homoenolate) is so reactive that it spontaneously reacts with the ketone to generate the more stable cyclopropanol tautomer. In the course of Loh’s efforts in developing the Umpolung chemistry of enone, they serendipitously synthesized the first water-tolerant, ketone-type indium homoenolate via the oxidative addition of In/InCl3 to enones (Scheme 435).54 A

Scheme 433

with the use of paraformaldeyde.617 However, in cases where 1bromo-1-nitroethane was used as substrate, only low to moderate diastereoselectivities of the desired products were obtained.645 They were also able to achieve an economical and improved version of the reaction by using a catalytic amount of indium (0.12 equiv) in combination with 10 equiv of zinc as reaction mediator.646 Most interestingly, under identical conditions, the use of chiral aldehydes derived from sugar led to the predominant or even exclusive diastereoselective formation of the corresponding anti product arising from steric interaction (Scheme 434),605,647 which can be elucidated by a Felkin−Anh model. A very recent development showed that imines (including imines derived from chiral aldehydes) reacted

Scheme 435

moderate to good yield of the indium homoenolate could be isolated when the reaction was performed in CH3CN/H2O for 24 h using 0.8 equiv of indium and 0.4 equiv of indium(III) chloride. In the NMR spectra of the indium homoenolate derived from ethyl vinyl ketone, signals from the CH2 attached to the indium were located significantly upfield at 0.83 ppm (t, J = 7.16 Hz) in 1H NMR and 8.4 ppm in 13C NMR. The reaction proceeded exclusively in aqueous medium. No reaction occurred in pure organic solvents such as THF, CH2Cl2, EtOAc, and CH3CN. Both indium and indium(III) chloride were necessary for the smooth progress of the reaction, and it could not do without either one of the two. Good results were also obtained when InCl and InCl2 were used in place of In/ InCl3; thus, InCl was suggested to be the actual mediator for the reaction. Unfortunately, no product was obtained when βsubstituted enone and α,β-unsaturated ester were used as substrate. The synthetic utility of the indium homoenolate was demonstrated through the synthesis of 1,4-dicarbonyl compounds via the palladium-catalyzed coupling of the indium homoenolate with acid chloride. The transformation of the enone to indium homoenolate also represents one of the few instances of Umpolung chemistry in enone, with inversion of its β-carbon polarity. On the basis of the X-ray crystal structure,

Scheme 434

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the indium homoenolate possesses a five-coordinated indium(III) center. Owing to the low reactivity of indium homoenolate, the palladium-catalyzed cross-coupling of indium homoenolate with aryl halides proceeded sluggishly in commonly used organic solvents such as THF ( Ar−Br ≈ Ar−OTf > Ar−Cl, which was similar to what was observed in cross-coupling reactions using other organometallic species. For the polyhalogenated 4-bromoiodobenzene, selective coupling 373


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gives rise to aryl-substituted dihydropyrans in moderate to good yields, accompanied by concomitant formation of

Organoindium Reagents: The Preparation and Application in Organic

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