Protic Ionic Liquids: Properties and Applications

Iron Catalysis in Organic Synthesis

140 years ago Adolf von Baeyer proposed the structure of a heteroaromatic compound which revolutionized organic and medical chemistry: indole. After more than a century, indole itself and the complexity of naturally occurring indole derivatives continue to inspire and influence developments in synthetic chemistry. In particular, the ubiquitous presence of indole rings in pharmaceuticals, agrochemicals, and functional materials are testament to the ever increasing interest in the design of mild and efficient synthetic routes to functionalized indole derivatives. This Review emphasizes the achievements in the selective catalytic functionalization of indoles (C-C bond-forming processes) over the last four years.

Catalytic Functionalization of Indoles in a New Dimension

The legacy of Gilbert Newton Lewis (1875-1946) pervades the lexicon of chemical bonding and reactivity. The power of his concept of donor-acceptor bonding is evident in the eponymous foundations of electron-pair acceptors (Lewis acids) and donors (Lewis bases). Lewis recognized that acids are not restricted to those substances that contain hydrogen (Bronsted acids), and helped overthrow the "modern cult of the proton". His discovery ushered in the use of Lewis acids as reagents and catalysts for organic reactions. However, in recent years, the recognition that Lewis bases can also serve in this capacity has grown enormously. Most importantly, it has become increasingly apparent that the behavior of Lewis bases as agents for promoting chemical reactions is not merely as an electronic complement of the cognate Lewis acids: in fact Lewis bases are capable of enhancing both the electrophilic and nucleophilic character of molecules to which they are bound. This diversity of behavior leads to a remarkable versatility for the catalysis of reactions by Lewis bases.

Lewis Base Catalysis in Organic Synthesis

3.1.2. Huisgen [3 + 2] Cycloaddition Reaction 6313 3.1.3. Claisen Rearrangement 6315 3.2. Multicomponent Reactions 6316 3.3. Nucleophilic Ring-Opening Reactions 6316 3.4. Wittig Reaction 6318 3.5. Bioorthogonal Reactions 6318 4. Catalyzed Reactions 6319 4.1. Metal-Catalyzed Reactions 6319 4.1.1. Pericyclic Reactions 6320 4.1.2. Arylation Reactions 6321 4.1.3. Olefin Metathesis 6323 4.1.4. Mizoroki-Heck Reaction 6324 4.1.5. Suzuki Reaction 6325 4.1.6. Sonogashira Reaction 6327 4.1.7. Transfer Hydrogenation 6327 4.1.8. Lewis Acid Catalysis 6328 4.2. Organocatalyzed Reactions 6330 4.2.1. Pericyclic Reactions 6330 4.2.2. Michael Reaction 6331 4.2.3. Mannich Reaction 6332 4.2.4. Aldol Reaction 6333 5. Conclusion 6334 6. Supporting Information Available 6335 7. References 6335

Water: Nature’s Reaction Enforcer—Comparative Effects for Organic Synthesis “In-Water” and “On-Water”

Sulfoxides were first introduced to the allylation of N-acylhydrazones with allyltrichlorosilanes as effective neutral coordinate-organocatalysts (NCOs). Both high diastereo- and enantioselectivity were attained when optically active chiral sulfoxides were used. Asymmetric crotylations using (Z)- and (E)-crotyltrichlorosilanes showed a high level of stereospecificity (Z → anti and E → syn) with high enantioselectivity.

Chiral sulfoxides as neutral coordinate-organocatalysts in asymmetric allylation of N-acylhydrazones using allyltrichlorosilanes.

Lewis acid catalysis has attracted much attention in organic synthesis as it often affords access to unique reactivity and selectivity under mild conditions. Although various kinds of Lewis acids have been developed and applied in industry, these Lewis acids must be generally used under strictly anhydrous conditions, as the presence of even a small amount of water interferes with the reactions due to preferential reaction of the Lewis acids with water rather than the substrates. In contrast to this, rare earth and other metal complexes have been found to be water-compatible. Furthermore, Bi(OTf) 3 - and Ga(OTf) 3 -basic ligand complexes have also been found to be stable in water, and have been used as water-compatible Lewis acids. This application is particularly significant, as Bi(OTf) 3 and Ga(OTf) 3 themselves are unstable in the presence of water, but are stabilized by the basic ligands. This observation has led to the development of a new approach to Lewis acid catalysis in which Lewis acids that are generally unstable in the presence of water are rendered amenable to aqueous systems when combined with basic ligands. In particular, the use of chiral basic ligands leading to new types of water-compatible chiral Lewis acids may enable a wide range of asymmetric catalysis in aqueous media.

New Entries to Water‐Compatible Lewis Acids

A Heterogeneous Silica‐Supported Scandium/Ionic Liquid Catalyst System for Organic Reactions in Water

Stereospecific, Enantioselective Allylation of α‐Hydrazono Esters by Using Allyltrichlorosilanes with BINAP Dioxides as Neutral‐Coordinate Organocatalysts

The use of Lewis acids as catalysts is one of the most powerful strategies in organic chemistry. In general, conventional Lewis acids such as AlCl3, TiCl4, BF3·OEt2, SnCl4, etc., require strictly anhydrous conditions because they immediately react with water in preference to the substrates, resulting in serious decomposition of the catalysts or the substrates. To address this issue, water-compatible Lewis acid catalyzed organic reactions have been intensively studied in the past decade. Considering the growing concern over environmental pollution, water is an ever more desirable alternative to organic solvents, as water is a clean, safe, and inexpensive solvent. Several surfactant-type catalysts derived from water-compatible Lewis acids have been developed, and catalytic asymmetric reactions have been achieved in water without requiring any organic cosolvents. These reactions proceeded smoothly by creating hydrophobic domains in the water to stabilize and concentrate the organic substrates, or by suppressing undesired reaction pathways that may occur in water. One of the key factors for these successes is the hydrophobicity of the substrates. Aqueous formaldehyde solutions (i.e. formalin) are one of the most important single carbon electrophiles and are representative of a hydrophilic substrate. As mentioned above, the hydrophobicity of the substrates is very important for organic reactions in water and hydrophilic substrates are often difficult to handle in water. Herein, we address this issue and describe a catalytic hydroxymethylation reaction with aqueous formaldehyde in which water is the sole solvent. First, we carried out the hydroxymethylation of silicon enolate 1 with 1 equivalent of formaldehyde (36% aqueous solution; aq. HCHO) in the presence of 2 mol% of scandium tris(dodecyl sulfate) (Sc(DS)3) [4] at a 1.0m concentration at 20 8C for 1 hour in water. The reaction proceeded sluggishly and afforded desired product 2 in poor yield. Increasing the amount of aq. HCHO to 3 equivalents improved the yield to 25%, but addition of more aq. HCHO did not result in increased amounts of the desired product (Figure 1a, navy blue). Gratifyingly, while optimizing the reaction conditions, we found that desired product 2 was obtained in 82% yield by using 5 equivalents of aq. HCHO and by extending the reaction time to 8 hours. Notably, under these conditions the competitive hydrolysis of silicon enolate 1 was observed. The loading levels of the catalyst also has an effect on the yield; the yield of 2 showed good correlations to the amount of Sc(DS)3 used, which ranged from 2, 5, 10, to 20 mol%. To improve the yield, we also investigated the concentration effect of aq. HCHO for each of the different Sc(DS)3 loadings (2, 5, 10, or 20 mol%) in the presence of 5 equivalents of aq. HCHO (Figure 1b). In the presence of 10 and 20 mol% of Sc(DS)3, the yields were improved to more than 80% as the concentrations increased to 2.0m, however, no additional improvement was observed when the concentration was increased to more than 2.0m. In the cases of 2 and 5 mol% of Sc(DS)3, the yields leveled off at much lower concentrations of 0.5m and 1.0m, respectively. These results indicated that Sc(DS)3 might be saturated by aq. HCHO. On the basis of the experiments described above, it can be said that despite the good solubility of HCHO in water, the amount of HCHO in the hydrophobic environment increases in the presence of Sc(DS)3 because of Lewis acid–Lewis base interactions between Sc(DS)3 and HCHO, therefore, allowing the reaction of HCHOwith silicon enolate 1 to proceed smoothly in water. After tuning the reaction conditions, we found that several silicon enolates reacted with aq. HCHO (5.0 equiv) in the presence of 5 mol% of Sc(DS)3 in water (1.0m) at 20 8C Figure 1. Hydroxymethylation of 1. a) Changes in yield as a function of the number of equivalents of HCHO at different catalyst loadings for a 1.0m solution monitored over 1 hour. b) Changes in yield as a function of concentration at different catalyst loadings for reaction containing 5.0 equivalents of HCHO monitored over 8 hours.

Chikako Ogawa

Papers

Chiral sulfoxides as neutral coordinate-organocatalysts in asymmetric allylation of N-acylhydrazones using allyltrichlorosilanes.

New Entries to Water‐Compatible Lewis Acids

A Heterogeneous Silica‐Supported Scandium/Ionic Liquid Catalyst System for Organic Reactions in Water

Stereospecific, Enantioselective Allylation of α‐Hydrazono Esters by Using Allyltrichlorosilanes with BINAP Dioxides as Neutral‐Coordinate Organocatalysts

Lewis Acid Catalysis in Water with a Hydrophilic Substrate: Scandium‐Catalyzed Hydroxymethylation with Aqueous Formaldehyde in Water